bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–04–14
sixty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A loneliness cure.
  2. Three possible muses.
  3. FOXO1 is a master regulator of memory programming in CAR T cells.
  4. Early-life exercise induces immunometabolic epigenetic modification enhancing anti-inflammatory immunity in middle-aged male mice.
  5. Daily briefing: Diabetes drug shows promise against Parkinson's.
  6. Nonlinear DNA methylation trajectories in aging male mice.
  7. Lipidomes define immune cell identity.
  8. OTUD5 promotes the inflammatory immune response by enhancing MyD88 oligomerization and Myddosome formation.
  9. The enduring neutrophil-stroma dance of multiple myeloma.
  10. Blocking cell death limits lung damage and inflammation from influenza.
  11. How to supercharge cancer-fighting cells: give them stem-cell skills.
  12. Gums make IL-23, no professionals needed.
  13. Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain.
  14. Immune dysregulation in long COVID.
  15. Parenchymal cues define Vegfa-driven venous angiogenesis by activating a sprouting competent venous endothelial subtype.
  16. Five biomarkers from one cerebrospinal fluid sample to stage Alzheimer's disease.
  17. Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations.
  18. Rejuvenating an old immune system.
  19. Daily briefing: Signs that ChatGPT is polluting peer review.
  20. Sea spray carries huge amounts of 'forever chemicals' into the air.
  21. Cryo-EM structure of the human Asc-1 transporter complex.
  22. Cell-type-specific mRNA transcription and degradation kinetics in zebrafish embryogenesis from metabolically labeled single-cell RNA-seq.
  23. Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function.
  24. Prey killing without invasion by Bdellovibrio bacteriovorus defective for a MIDAS-family adhesin.
  25. Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation.
  26. Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
  27. HDAC3 stokes microglia in stroke.
  28. Biological age surges in survivors of childhood cancer.
  29. Transcriptional bodies manage tight resources.
  30. A call for accessible tools to unlock single-cell immunometabolism research.
  31. Randomness in computation wins computer-science 'Nobel'.
  32. A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility.
  33. Single-cell systems pharmacology identifies development-driven drug response and combination therapy in B cell acute lymphoblastic leukemia.
  34. Bitter taste receptors are even older than scientists thought.
  35. scGHOST: identifying single-cell 3D genome subcompartments.
  36. Problem choice and decision trees in science and engineering.
  37. Integrated proteomics reveals autophagy landscape and an autophagy receptor controlling PKA-RI complex homeostasis in neurons.
  38. Kinetic trapping organizes actin filaments within liquid-like protein droplets.
  39. Bird flu outbreak in US cows: why scientists are concerned.
  40. Human MHC Class II and Invariant Chain Knock-in Mice Mimic Rheumatoid Arthritis with Allele Restriction in Immune Response and Arthritis Association.
  41. Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.
  42. LDL receptor-related protein 5 selectively transports unesterified polyunsaturated fatty acids to intracellular compartments.
  43. TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells.
  44. DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues.
  45. Diverse and abundant phages exploit conjugative plasmids.
  46. Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
  47. Closing the loop on thermoset plastic recycling.
  48. Single-cell long-read sequencing-based mapping reveals specialized splicing patterns in developing and adult mouse and human brain.
  49. Pushing the bounds on dimensionality.
  50. Type I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection.
  51. Adding a transcription-coupled repair pathway.
  52. Genetic risk variants lead to type 2 diabetes development through different pathways.
  53. How two PhD students overcame the odds to snag tenure-track jobs.
  54. MEF2C regulates NK cell effector functions through control of lipid metabolism.
  55. Total solar eclipse 2024: what dazzled scientists.
  56. How to plug the female mentoring gap in Latin American science.
  57. A genome-wide association study provides insights into the genetic etiology of 57 essential and non-essential trace elements in humans.
  58. This fMRI technique promised to transform brain research - why can no one replicate it?
  59. ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D.
  60. Spatiotemporal immune atlas of a clinical-grade gene-edited pig-to-human kidney xenotransplant.
  61. Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection.
  1. Science. 2024 Apr 12. 384(6692): 242
    A loneliness cure.
    Dequn Teng.
      
    DOI:  https://doi.org/10.1126/science.adp6654
  2. Nature. 2024 Apr 10.
    Three possible muses.
    Matt Tighe.
      
    Keywords:  Arts; Culture
    DOI:  https://doi.org/10.1038/d41586-024-00921-z
  3. Nature. 2024 Apr 10.
    FOXO1 is a master regulator of memory programming in CAR T cells.
    Alexander E Doan, Katherine P Mueller, Andy Y Chen, Geoffrey T Rouin, Yingshi Chen, Bence Daniel, John Lattin, Martina Markovska, Brett Mozarsky, Jose Arias-Umana, Robert Hapke, In-Young Jung, Alice Wang, Peng Xu, Dorota Klysz, Gabrielle Zuern, Malek Bashti, Patrick J Quinn, Zhuang Miao, Katalin Sandor, Wenxi Zhang, Gregory M Chen, Faith Ryu, Meghan Logun, Junior Hall, Kai Tan, Stephan A Grupp, Susan E McClory, Caleb A Lareau, Joseph A Fraietta, Elena Sotillo, Ansuman T Satpathy, Crystal L Mackall, Evan W Weber.
      A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2-6, suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.
    DOI:  https://doi.org/10.1038/s41586-024-07300-8
  4. Nat Commun. 2024 Apr 10. 15(1): 3103
    Early-life exercise induces immunometabolic epigenetic modification enhancing anti-inflammatory immunity in middle-aged male mice.
    Nini Zhang, Xinpei Wang, Mengya Feng, Min Li, Jing Wang, Hongyan Yang, Siyu He, Ziqi Xia, Lei Shang, Xun Jiang, Mao Sun, Yuanming Wu, Chaoxue Ren, Xing Zhang, Jia Li, Feng Gao.
      Exercise is usually regarded to have short-term beneficial effects on immune health. Here we show that early-life regular exercise exerts long-term beneficial effects on inflammatory immunity. Swimming training for 3 months in male mice starting from 1-month-old curbs cytokine response and mitigates sepsis when exposed to lipopolysaccharide challenge, even after an 11-month interval of detraining. Metabolomics analysis of serum and liver identifies pipecolic acid, a non-encoded amino acid, as a pivotal metabolite responding to early-life regular exercise. Importantly, pipecolic acid reduces inflammatory cytokines in bone marrow-derived macrophages and alleviates sepsis via inhibiting mTOR complex 1 signaling. Moreover, early-life exercise increases histone 3 lysine 4 trimethylation at the promoter of Crym in the liver, an enzyme responsible for catalyzing pipecolic acid production. Liver-specific knockdown of Crym in adult mice abolishes this early exercise-induced protective effects. Our findings demonstrate that early-life regular exercise enhances anti-inflammatory immunity during middle-aged phase in male mice via epigenetic immunometabolic modulation, in which hepatic pipecolic acid production has a pivotal function.
    DOI:  https://doi.org/10.1038/s41467-024-47458-3
  5. Nature. 2024 Apr 05.
    Daily briefing: Diabetes drug shows promise against Parkinson's.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-01049-w
  6. Nat Commun. 2024 Apr 09. 15(1): 3074
    Nonlinear DNA methylation trajectories in aging male mice.
    Maja Olecka, Alena van Bömmel, Lena Best, Madlen Haase, Silke Foerste, Konstantin Riege, Thomas Dost, Stefano Flor, Otto W Witte, Sören Franzenburg, Marco Groth, Björn von Eyss, Christoph Kaleta, Christiane Frahm, Steve Hoffmann.
      Although DNA methylation data yields highly accurate age predictors, little is known about the dynamics of this quintessential epigenomic biomarker during lifespan. To narrow the gap, we investigate the methylation trajectories of male mouse colon at five different time points of aging. Our study indicates the existence of sudden hypermethylation events at specific stages of life. Precisely, we identify two epigenomic switches during early-to-midlife (3-9 months) and mid-to-late-life (15-24 months) transitions, separating the rodents' life into three stages. These nonlinear methylation dynamics predominantly affect genes associated with the nervous system and enrich in bivalently marked chromatin regions. Based on groups of nonlinearly modified loci, we construct a clock-like classifier STageR (STage of aging estimatoR) that accurately predicts murine epigenetic stage. We demonstrate the universality of our clock in an independent mouse cohort and with publicly available datasets.
    DOI:  https://doi.org/10.1038/s41467-024-47316-2
  7. Nat Cell Biol. 2024 Apr 08.
    Lipidomes define immune cell identity.
    Kandice R Levental, Whitney S Henry.
      
    DOI:  https://doi.org/10.1038/s41556-024-01398-8
  8. Cell Death Differ. 2024 Apr 11.
    OTUD5 promotes the inflammatory immune response by enhancing MyD88 oligomerization and Myddosome formation.
    Yaxing Liu, Jiahua Yuan, Yuling Zhang, Fei Qin, Xuemei Bai, Wanwei Sun, Tian Chen, Feng Liu, Yi Zheng, Xiaopeng Qi, Wei Zhao, Bingyu Liu, Chengjiang Gao.
      Myddosome is an oligomeric complex required for the transmission of inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for the self-assemble of Myddosome proteins and regulation of intracellular signaling remains poorly understood. Here, we identify OTUD5 acts as an essential regulator for MyD88 oligomerization and Myddosome formation. OTUD5 directly interacts with MyD88 and cleaves its K11-linked polyubiquitin chains at Lys95, Lys231 and Lys250. This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-κB and MAPK signaling and production of inflammatory cytokines. Consistently, Otud5-deficient mice are less susceptible to LPS- and CLP-induced sepsis. Taken together, our findings reveal a positive regulatory role of OTUD5 in MyD88 oligomerization and Myddosome formation, which provides new sights into the treatment of inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41418-024-01293-7
  9. Nat Immunol. 2024 Apr 10.
    The enduring neutrophil-stroma dance of multiple myeloma.
    Daniela Cerezo-Wallis, Iván Ballesteros.
      
    DOI:  https://doi.org/10.1038/s41590-024-01810-3
  10. Nature. 2024 Apr 10.
    Blocking cell death limits lung damage and inflammation from influenza.
    Nishma Gupta, John Silke.
      
    Keywords:  Immunology; Medical research; Virology
    DOI:  https://doi.org/10.1038/d41586-024-00910-2
  11. Nature. 2024 Apr 10.
    How to supercharge cancer-fighting cells: give them stem-cell skills.
    Sara Reardon.
      
    Keywords:  Cancer; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-01043-2
  12. Immunity. 2024 Apr 09. pii: S1074-7613(24)00130-4. [Epub ahead of print]57(4): 832-834
    Gums make IL-23, no professionals needed.
    Mandy J McGeachy.
      IL-23 activates pathogenic Th17 cells to drive inflammatory disease at barrier surfaces. Kim et al. now identify oral epithelial cells as the critical producers of IL-23 in human and mouse periodontitis, linking microbial dysbiosis to non-hematopoietic regulation of IL-17-associated inflammation.
    DOI:  https://doi.org/10.1016/j.immuni.2024.03.009
  13. Nature. 2024 Apr 10.
    Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain.
    Changuk Chung, Xiaoxu Yang, Robert F Hevner, Katie Kennedy, Keng Ioi Vong, Yang Liu, Arzoo Patel, Rahul Nedunuri, Scott T Barton, Geoffroy Noel, Chelsea Barrows, Valentina Stanley, Swapnil Mittal, Martin W Breuss, Johannes C M Schlachetzki, Stephen F Kingsmore, Joseph G Gleeson.
      Debate remains around the anatomical origins of specific brain cell subtypes and lineage relationships within the human forebrain1-7. Thus, direct observation in the mature human brain is critical for a complete understanding of its structural organization and cellular origins. Here we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific mosaic variant barcode analysis. From four hemispheres and two different human neurotypical donors, we identified 287 and 780 mosaic variants, respectively, that were used to deconvolve clonal dynamics. Clonal spread and allele fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted than resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome transcriptome analysis at both a cell-type-specific and a single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1+ inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of mosaic variants across 17 locations within one parietal lobe reveals that restriction of clonal spread in the anterior-posterior axis precedes restriction in the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain.
    DOI:  https://doi.org/10.1038/s41586-024-07292-5
  14. Nat Immunol. 2024 Apr;25(4): 587-589
    Immune dysregulation in long COVID.
    Laura Ceglarek, Onur Boyman.
      
    DOI:  https://doi.org/10.1038/s41590-024-01795-z
  15. Nat Commun. 2024 Apr 10. 15(1): 3118
    Parenchymal cues define Vegfa-driven venous angiogenesis by activating a sprouting competent venous endothelial subtype.
    Laetitia Préau, Anna Lischke, Melanie Merkel, Neslihan Oegel, Maria Weissenbruch, Andria Michael, Hongryeol Park, Dietmar Gradl, Christian Kupatt, Ferdinand le Noble.
      Formation of organo-typical vascular networks requires cross-talk between differentiating parenchymal cells and developing blood vessels. Here we identify a Vegfa driven venous sprouting process involving parenchymal to vein cross-talk regulating venous endothelial Vegfa signaling strength and subsequent formation of a specialized angiogenic cell, prefabricated with an intact lumen and pericyte coverage, termed L-Tip cell. L-Tip cell selection in the venous domain requires genetic interaction between vascular Aplnra and Kdrl in a subset of venous endothelial cells and exposure to parenchymal derived Vegfa and Apelin. Parenchymal Esm1 controls the spatial positioning of venous sprouting by fine-tuning local Vegfa availability. These findings may provide a conceptual framework for understanding how Vegfa generates organo-typical vascular networks based on the selection of competent endothelial cells, induced via spatio-temporal control of endothelial Kdrl signaling strength involving multiple parenchymal derived cues generated in a tissue dependent metabolic context.
    DOI:  https://doi.org/10.1038/s41467-024-47434-x
  16. Nat Aging. 2024 Apr 09.
    Five biomarkers from one cerebrospinal fluid sample to stage Alzheimer's disease.
      
    DOI:  https://doi.org/10.1038/s43587-024-00618-y
  17. Nat Commun. 2024 Apr 10. 15(1): 3111
    Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations.
    Jiuwei Lu, Yiran Guo, Jiekai Yin, Jianbin Chen, Yinsheng Wang, Gang Greg Wang, Jikui Song.
      DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.
    DOI:  https://doi.org/10.1038/s41467-024-47398-y
  18. Nat Rev Immunol. 2024 Apr 09.
    Rejuvenating an old immune system.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-024-01031-7
  19. Nature. 2024 Apr 11.
    Daily briefing: Signs that ChatGPT is polluting peer review.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-01106-4
  20. Nature. 2024 Apr 05.
    Sea spray carries huge amounts of 'forever chemicals' into the air.
      
    Keywords:  Atmospheric science
    DOI:  https://doi.org/10.1038/d41586-024-01030-7
  21. Nat Commun. 2024 Apr 08. 15(1): 3036
    Cryo-EM structure of the human Asc-1 transporter complex.
    Yaning Li, Yingying Guo, Angelika Bröer, Lu Dai, Stefan Brӧer, Renhong Yan.
      The Alanine-Serine-Cysteine transporter 1 (Asc-1 or SLC7A10) forms a crucial heterodimeric transporter complex with 4F2hc (SLC3A2) through a covalent disulfide bridge. This complex enables the sodium-independent transport of small neutral amino acids, including L-Alanine (L-Ala), Glycine (Gly), and D-Serine (D-Ser), within the central nervous system (CNS). D-Ser and Gly are two key endogenous glutamate co-agonists that activate N-methyl-d-aspartate (NMDA) receptors by binding to the allosteric site. Mice deficient in Asc-1 display severe symptoms such as tremors, ataxia, and seizures, leading to early postnatal death. Despite its physiological importance, the functional mechanism of the Asc-1-4F2hc complex has remained elusive. Here, we present cryo-electron microscopy (cryo-EM) structures of the human Asc-1-4F2hc complex in its apo state, D-Ser bound state, and L-Ala bound state, resolved at 3.6 Å, 3.5 Å, and 3.4 Å, respectively. Through detailed structural analysis and transport assays, we uncover a comprehensive alternating access mechanism that underlies conformational changes in the complex. In summary, our findings reveal the architecture of the Asc-1 and 4F2hc complex and provide valuable insights into substrate recognition and the functional cycle of this essential transporter complex.
    DOI:  https://doi.org/10.1038/s41467-024-47468-1
  22. Nat Commun. 2024 Apr 10. 15(1): 3104
    Cell-type-specific mRNA transcription and degradation kinetics in zebrafish embryogenesis from metabolically labeled single-cell RNA-seq.
    Lior Fishman, Avani Modak, Gal Nechooshtan, Talya Razin, Florian Erhard, Aviv Regev, Jeffrey A Farrell, Michal Rabani.
      During embryonic development, pluripotent cells assume specialized identities by adopting particular gene expression profiles. However, systematically dissecting the relative contributions of mRNA transcription and degradation to shaping those profiles remains challenging, especially within embryos with diverse cellular identities. Here, we combine single-cell RNA-Seq and metabolic labeling to capture temporal cellular transcriptomes of zebrafish embryos where newly-transcribed (zygotic) and pre-existing (maternal) mRNA can be distinguished. We introduce kinetic models to quantify mRNA transcription and degradation rates within individual cell types during their specification. These models reveal highly varied regulatory rates across thousands of genes, coordinated transcription and destruction rates for many transcripts, and link differences in degradation to specific sequence elements. They also identify cell-type-specific differences in degradation, namely selective retention of maternal transcripts within primordial germ cells and enveloping layer cells, two of the earliest specified cell types. Our study provides a quantitative approach to study mRNA regulation during a dynamic spatio-temporal response.
    DOI:  https://doi.org/10.1038/s41467-024-47290-9
  23. Cell Rep. 2024 Apr 10. pii: S2211-1247(24)00432-7. [Epub ahead of print]43(4): 114104
    Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function.
    Jun Takahashi, Takafumi Suzuki, Miu Sato, Shuji Nitta, Nahoko Yaguchi, Tatsuki Muta, Kouhei Tsuchida, Hiromi Suda, Masanobu Morita, Shin Hamada, Atsushi Masamune, Satoru Takahashi, Takashi Kamei, Masayuki Yamamoto.
      Clinical evidence has revealed that high-level activation of NRF2 caused by somatic mutations in NRF2 (NFE2L2) is frequently detected in esophageal squamous cell carcinoma (ESCC), whereas that caused by somatic mutations in KEAP1, a negative regulator of NRF2, is not. Here, we aspire to generate a mouse model of NRF2-activated ESCC using the cancer-derived NRF2L30F mutation and cancer driver mutant TRP53R172H. Concomitant expression of NRF2L30F and TRP53R172H results in formation of NRF2-activated ESCC-like lesions. In contrast, while squamous-cell-specific deletion of KEAP1 induces similar NRF2 hyperactivation, the loss of KEAP1 combined with expression of TRP53R172H does not elicit the formation of ESCC-like lesions. Instead, KEAP1-deleted cells disappear from the esophageal epithelium over time. These findings demonstrate that, while cellular NRF2 levels are similarly induced, NRF2 gain of function and KEAP1 loss of function elicits distinct fates of squamous cells. The NRF2L30F mutant mouse model developed here will be instrumental in elucidating the mechanistic basis leading to NRF2-activated ESCC.
    Keywords:  CP: Cancer
    DOI:  https://doi.org/10.1016/j.celrep.2024.114104
  24. Nat Commun. 2024 Apr 09. 15(1): 3078
    Prey killing without invasion by Bdellovibrio bacteriovorus defective for a MIDAS-family adhesin.
    Jess Tyson, Paul Radford, Carey Lambert, Rob Till, Simona G Huwiler, Andrew L Lovering, R Elizabeth Sockett.
      The bacterium Bdellovibrio bacteriovorus is a predator of other Gram-negative bacteria. The predator invades the prey's periplasm and modifies the prey's cell wall, forming a rounded killed prey, or bdelloplast, containing a live B. bacteriovorus. Redundancy in adhesive processes makes invasive mutants rare. Here, we identify a MIDAS adhesin family protein, Bd0875, that is expressed at the predator-prey invasive junction and is important for successful invasion of prey. A mutant strain lacking bd0875 is still able to form round, dead bdelloplasts; however, 10% of the bdelloplasts do not contain B. bacteriovorus, indicative of an invasion defect. Bd0875 activity requires the conserved MIDAS motif, which is linked to catch-and-release activity of MIDAS proteins in other organisms. A proteomic analysis shows that the uninvaded bdelloplasts contain B. bacteriovorus proteins, which are likely secreted into the prey by the Δbd0875 predator during an abortive invasion period. Thus, secretion of proteins into the prey seems to be sufficient for prey killing, even in the absence of a live predator inside the prey periplasm.
    DOI:  https://doi.org/10.1038/s41467-024-47412-3
  25. Sci Immunol. 2024 Apr 12. 9(94): eadi1023
    Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation.
    Ioanna Tiniakou, Pei-Feng Hsu, Lorena S Lopez-Zepeda, Görkem Garipler, Eduardo Esteva, Nicholas M Adams, Geunhyo Jang, Chetna Soni, Colleen M Lau, Fan Liu, Alireza Khodadadi-Jamayran, Tori C Rodrick, Drew Jones, Aristotelis Tsirigos, Uwe Ohler, Mark T Bedford, Stephen D Nimer, Vesa Kaartinen, Esteban O Mazzoni, Boris Reizis.
      The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected Flt3L-driven DC differentiation using CRISPR-Cas9-based screening. Genome-wide screening identified multiple regulators of DC differentiation including subunits of TSC and GATOR1 complexes, which restricted progenitor growth but enabled DC differentiation by inhibiting mTOR signaling. An orthogonal screen identified the transcriptional repressor Trim33 (TIF-1γ) as a regulator of DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, deletion of Trim33 caused rapid loss of DC progenitors, pDCs, and the cross-presenting cDC1 subset. Trim33-deficient Flt3+ progenitors up-regulated pro-inflammatory and macrophage-specific genes but failed to induce the DC differentiation program. Collectively, these data elucidate mechanisms that control Flt3L-driven differentiation of the entire DC lineage and identify Trim33 as its essential regulator.
    DOI:  https://doi.org/10.1126/sciimmunol.adi1023
  26. Nat Cell Biol. 2024 Apr 09.
    Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
    Ao Liu, Frieda Kage, Asan F Abdulkareem, Mac Pholo Aguirre-Huamani, Gracie Sapp, Halil Aydin, Henry N Higgs.
      Mitochondrial fission occurs in many cellular processes, but the regulation of fission is poorly understood. We show that long-chain acyl-coenzyme A (LCACA) activates two related mitochondrial fission proteins, MiD49 and MiD51, by inducing their oligomerization, which activates their ability to stimulate the DRP1 GTPase. The 1:1 stoichiometry of LCACA:MiD in the oligomer suggests interaction in the previously identified nucleotide-binding pocket, and a point mutation in this pocket reduces LCACA binding and LCACA-induced oligomerization for MiD51. In cells, this LCACA binding mutant does not assemble into puncta on mitochondria or rescue MiD49/51 knockdown effects on mitochondrial length and DRP1 recruitment. Furthermore, cellular treatment with BSA-bound oleic acid, which causes increased LCACA, promotes mitochondrial fission in an MiD49/51-dependent manner. These results suggest that LCACA is an endogenous ligand for MiDs, inducing mitochondrial fission and providing a potential mechanism for fatty-acid-induced mitochondrial division. Finally, MiD49 or MiD51 oligomers synergize with Mff, but not with actin filaments, in DRP1 activation, suggesting distinct pathways for DRP1 activation.
    DOI:  https://doi.org/10.1038/s41556-024-01400-3
  27. Nat Neurosci. 2024 Apr;27(4): 606
    HDAC3 stokes microglia in stroke.
    George Andrew S Inglis.
      
    DOI:  https://doi.org/10.1038/s41593-024-01622-6
  28. Nature. 2024 Apr 11.
    Biological age surges in survivors of childhood cancer.
      
    Keywords:  Cancer
    DOI:  https://doi.org/10.1038/d41586-024-01033-4
  29. Nat Cell Biol. 2024 Apr 08.
    Transcriptional bodies manage tight resources.
    Natalia Stec, Adam Klosin.
      
    DOI:  https://doi.org/10.1038/s41556-024-01395-x
  30. Nat Metab. 2024 Apr 11.
    A call for accessible tools to unlock single-cell immunometabolism research.
    Jason Cosgrove, Antoine Marçais, Felix J Hartmann, Andreas Bergthaler, Ivan Zanoni, Mauro Corrado, Leïla Perié, Nina Cabezas-Wallscheid, Philippe Bousso, Theodore Alexandrov, Tammy Kielian, Nuria Martínez-Martín, Christiane A Opitz, Costas A Lyssiotis, Rafael J Argüello, Jan Van den Bossche.
      
    DOI:  https://doi.org/10.1038/s42255-024-01031-w
  31. Nature. 2024 Apr 10.
    Randomness in computation wins computer-science 'Nobel'.
    Davide Castelvecchi.
      
    Keywords:  Mathematics and computing
    DOI:  https://doi.org/10.1038/d41586-024-01055-y
  32. Nat Cell Biol. 2024 Apr 08.
    A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility.
    Pooranee K Morgan, Gerard Pernes, Kevin Huynh, Corey Giles, Sudip Paul, Adam Alexander T Smith, Natalie A Mellett, Amy Liang, Tilly van Buuren-Milne, Camilla Bertuzzo Veiga, Thomas J C Collins, Yangsong Xu, Man K S Lee, T Michael De Silva, Peter J Meikle, Graeme I Lancaster, Andrew J Murphy.
      The cellular lipidome comprises thousands of unique lipid species. Here, using mass spectrometry-based targeted lipidomics, we characterize the lipid landscape of human and mouse immune cells ( www.cellularlipidatlas.com ). Using this resource, we show that immune cells have unique lipidomic signatures and that processes such as activation, maturation and development impact immune cell lipid composition. To demonstrate the potential of this resource to provide insights into immune cell biology, we determine how a cell-specific lipid trait-differences in the abundance of polyunsaturated fatty acid-containing glycerophospholipids (PUFA-PLs)-influences immune cell biology. First, we show that differences in PUFA-PL content underpin the differential susceptibility of immune cells to ferroptosis. Second, we show that low PUFA-PL content promotes resistance to ferroptosis in activated neutrophils. In summary, we show that the lipid landscape is a defining feature of immune cell identity and that cell-specific lipid phenotypes underpin aspects of immune cell physiology.
    DOI:  https://doi.org/10.1038/s41556-024-01377-z
  33. Cancer Cell. 2024 Apr 08. pii: S1535-6108(24)00088-6. [Epub ahead of print]42(4): 552-567.e6
    Single-cell systems pharmacology identifies development-driven drug response and combination therapy in B cell acute lymphoblastic leukemia.
    Xin Huang, Yizhen Li, Jingliao Zhang, Lei Yan, Huanbin Zhao, Liang Ding, Sheetal Bhatara, Xu Yang, Satoshi Yoshimura, Wenjian Yang, Seth E Karol, Hiroto Inaba, Charles Mullighan, Mark Litzow, Xiaofan Zhu, Yingchi Zhang, Wendy Stock, Nitin Jain, Elias Jabbour, Steven M Kornblau, Marina Konopleva, Ching-Hon Pui, Elisabeth Paietta, William Evans, Jiyang Yu, Jun J Yang.
      Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.
    Keywords:  B cell development; L-asparaginase; NetBID2; acute lymphoblastic leukemia; developmental origins; hidden driver; single-cell multiome; single-cell systems pharmacology; venetoclax
    DOI:  https://doi.org/10.1016/j.ccell.2024.03.003
  34. Nature. 2024 Apr 11.
    Bitter taste receptors are even older than scientists thought.
      
    Keywords:  Sensory systems
    DOI:  https://doi.org/10.1038/d41586-024-01031-6
  35. Nat Methods. 2024 Apr 08.
    scGHOST: identifying single-cell 3D genome subcompartments.
    Kyle Xiong, Ruochi Zhang, Jian Ma.
      Single-cell Hi-C (scHi-C) technologies allow for probing of genome-wide cell-to-cell variability in three-dimensional (3D) genome organization from individual cells. Computational methods have been developed to reveal single-cell 3D genome features based on scHi-C, including A/B compartments, topologically associating domains and chromatin loops. However, no method exists for annotating single-cell subcompartments, which is important for understanding chromosome spatial localization in single cells. Here we present scGHOST, a single-cell subcompartment annotation method using graph embedding with constrained random walk sampling. Applications of scGHOST to scHi-C data and contact maps derived from single-cell 3D genome imaging demonstrate reliable identification of single-cell subcompartments, offering insights into cell-to-cell variability of nuclear subcompartments. Using scHi-C data from complex tissues, scGHOST identifies cell-type-specific or allele-specific subcompartments linked to gene transcription across various cell types and developmental stages, suggesting functional implications of single-cell subcompartments. scGHOST is an effective method for annotating single-cell 3D genome subcompartments in a broad range of biological contexts.
    DOI:  https://doi.org/10.1038/s41592-024-02230-9
  36. Cell. 2024 Apr 11. pii: S0092-8674(24)00304-0. [Epub ahead of print]187(8): 1828-1833
    Problem choice and decision trees in science and engineering.
    Michael A Fischbach.
      Scientists and engineers often spend days choosing a problem and years solving it. This imbalance limits impact. Here, we offer a framework for problem choice: prompts for ideation, guidelines for evaluating impact and likelihood of success, the importance of fixing one parameter at a time, and opportunities afforded by failure.
    DOI:  https://doi.org/10.1016/j.cell.2024.03.012
  37. Nat Commun. 2024 Apr 10. 15(1): 3113
    Integrated proteomics reveals autophagy landscape and an autophagy receptor controlling PKA-RI complex homeostasis in neurons.
    Xiaoting Zhou, You-Kyung Lee, Xianting Li, Henry Kim, Carlos Sanchez-Priego, Xian Han, Haiyan Tan, Suiping Zhou, Yingxue Fu, Kerry Purtell, Qian Wang, Gay R Holstein, Beisha Tang, Junmin Peng, Nan Yang, Zhenyu Yue.
      Autophagy is a conserved, catabolic process essential for maintaining cellular homeostasis. Malfunctional autophagy contributes to neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we report a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and brain LC3-interactome reveals roles of neuronal autophagy in targeting proteins of multiple cellular organelles/pathways, including endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) for degradation. By combining phosphoproteomics and functional analysis in human and mouse neurons, we uncovered a function of neuronal autophagy in controlling cAMP-PKA and c-FOS-mediated neuronal activity through selective degradation of the protein kinase A - cAMP-binding regulatory (R)-subunit I (PKA-RI) complex. Lack of AKAP11 causes accumulation of the PKA-RI complex in the soma and neurites, demonstrating a constant clearance of PKA-RI complex through AKAP11-mediated degradation in neurons. Our study thus reveals the landscape of autophagy degradation in human neurons and identifies a physiological function of autophagy in controlling homeostasis of PKA-RI complex and specific PKA activity in neurons.
    DOI:  https://doi.org/10.1038/s41467-024-47440-z
  38. Nat Commun. 2024 Apr 11. 15(1): 3139
    Kinetic trapping organizes actin filaments within liquid-like protein droplets.
    Aravind Chandrasekaran, Kristin Graham, Jeanne C Stachowiak, Padmini Rangamani.
      Several actin-binding proteins (ABPs) phase separate to form condensates capable of curating the actin network shapes. Here, we use computational modeling to understand the principles of actin network organization within VASP condensate droplets. Our simulations reveal that the different actin shapes, namely shells, rings, and mixture states are highly dependent on the kinetics of VASP-actin interactions, suggesting that they arise from kinetic trapping. Specifically, we show that reducing the residence time of VASP on actin filaments reduces degree of bundling, thereby promoting assembly of shells rather than rings. We validate the model predictions experimentally using a VASP-mutant with decreased bundling capability. Finally, we investigate the ring opening within deformed droplets and found that the sphere-to-ellipsoid transition is favored under a wide range of filament lengths while the ellipsoid-to-rod transition is only permitted when filaments have a specific range of lengths. Our findings highlight key mechanisms of actin organization within phase-separated ABPs.
    DOI:  https://doi.org/10.1038/s41467-024-46726-6
  39. Nature. 2024 Apr 08.
    Bird flu outbreak in US cows: why scientists are concerned.
    Max Kozlov, Smriti Mallapaty.
      
    Keywords:  Epidemiology; Evolution; Infection; Virology
    DOI:  https://doi.org/10.1038/d41586-024-01036-1
  40. Adv Sci (Weinh). 2024 Apr 11. e2401513
    Human MHC Class II and Invariant Chain Knock-in Mice Mimic Rheumatoid Arthritis with Allele Restriction in Immune Response and Arthritis Association.
    Laura Romero-Castillo, Taotao Li, Nhu-Nguyen Do, Outi Sareila, Bingze Xu, Viktoria Hennings, Zhongwei Xu, Carolin Svensson, Ana Oliveira-Coelho, Zeynep Sener, Vilma Urbonaviciute, Olov Ekwall, Harald Burkhardt, Rikard Holmdahl.
      Transgenic mice expressing human major histocompatibility complex class II (MHCII) risk alleles are widely used in autoimmune disease research, but limitations arise due to non-physiologic expression. To address this, physiologically relevant mouse models are established via knock-in technology to explore the role of MHCII in diseases like rheumatoid arthritis. The gene sequences encoding the ectodomains are replaced with the human DRB1*04:01 and 04:02 alleles, DRA, and CD74 (invariant chain) in C57BL/6N mice. The collagen type II (Col2a1) gene is modified to mimic human COL2. Importantly, DRB1*04:01 knock-in mice display physiologic expression of human MHCII also on thymic epithelial cells, in contrast to DRB1*04:01 transgenic mice. Humanization of the invariant chain enhances MHCII expression on thymic epithelial cells, increases mature B cell numbers in spleen, and improves antigen presentation. To validate its functionality, the collagen-induced arthritis (CIA) model is used, where DRB1*04:01 expression led to a higher susceptibility to arthritis, as compared with mice expressing DRB1*04:02. In addition, the humanized T cell epitope on COL2 allows autoreactive T cell-mediated arthritis development. In conclusion, the humanized knock-in mouse faithfully expresses MHCII, confirming the DRB1*04:01 alleles role in rheumatoid arthritis and being also useful for studying MHCII-associated diseases.
    Keywords:  CIA; DTH; MHC class II; autoimmune diseases; humanized mice; rheumatoid arthritis
    DOI:  https://doi.org/10.1002/advs.202401513
  41. Nat Immunol. 2024 Apr 12.
    Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.
    Hirotsugu Oda, Kalpana Manthiram, Pallavi Pimpale Chavan, Eva Rieser, Önay Veli, Öykü Kaya, Charles Rauch, Shuichiro Nakabo, Hye Sun Kuehn, Mariël Swart, Yanli Wang, Nisa Ilgim Çelik, Anne Molitor, Vahid Ziaee, Nasim Movahedi, Mohammad Shahrooei, Nima Parvaneh, Nasrin Alipour-Olyei, Raphael Carapito, Qin Xu, Silvia Preite, David B Beck, Jae Jin Chae, Michele Nehrebecky, Amanda K Ombrello, Patrycja Hoffmann, Tina Romeo, Natalie T Deuitch, Brynja Matthíasardóttir, James Mullikin, Hirsh Komarow, Jennifer Stoddard, Julie Niemela, Kerry Dobbs, Colin L Sweeney, Holly Anderton, Kate E Lawlor, Hiroyuki Yoshitomi, Dan Yang, Manfred Boehm, Jeremy Davis, Pamela Mudd, Davide Randazzo, Wanxia Li Tsai, Massimo Gadina, Mariana J Kaplan, Junya Toguchida, Christian T Mayer, Sergio D Rosenzweig, Luigi D Notarangelo, Kazuhiro Iwai, John Silke, Pamela L Schwartzberg, Bertrand Boisson, Jean-Laurent Casanova, Seiamak Bahram, Anand Prahalad Rao, Nieves Peltzer, Henning Walczak, Najoua Lalaoui, Ivona Aksentijevich, Daniel L Kastner.
      The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.
    DOI:  https://doi.org/10.1038/s41590-024-01817-w
  42. Nat Commun. 2024 Apr 09. 15(1): 3068
    LDL receptor-related protein 5 selectively transports unesterified polyunsaturated fatty acids to intracellular compartments.
    Wenwen Tang, Yi Luan, Qianying Yuan, Ao Li, Song Chen, Stanley Menacherry, Lawrence Young, Dianqing Wu.
      Polyunsaturated fatty acids (PUFAs), which cannot be synthesized by animals and must be supplied from the diet, have been strongly associated with human health. However, the mechanisms for their accretion remain poorly understood. Here, we show that LDL receptor-related protein 5 (LRP5), but not its homolog LRP6, selectively transports unesterified PUFAs into a number of cell types. The LDLa ligand-binding repeats of LRP5 directly bind to PUFAs and are required and sufficient for PUFA transport. In contrast to the known PUFA transporters Mfsd2a, CD36 and FATP2, LRP5 transports unesterified PUFAs via internalization to intracellular compartments including lysosomes, and n-3 PUFAs depend on this transport mechanism to inhibit mTORC1. This LRP5-mediated PUFA transport mechanism suppresses extracellular trap formation in neutrophils and protects mice from myocardial injury during ischemia-reperfusion. Thus, this study reveals a biologically important mechanism for unesterified PUFA transport to intracellular compartments.
    DOI:  https://doi.org/10.1038/s41467-024-47262-z
  43. J Biol Chem. 2024 Apr 08. pii: S0021-9258(24)01771-X. [Epub ahead of print] 107270
    TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells.
    Suli Lv, Zongbiao Zhang, Zhenyong Li, Qian Ke, Xianyun Ma, Neng Li, Xuefeng Zhao, Qingli Zou, Lidong Sun, Tanjing Song.
      Higher demand for nutrients including glucose is characteristic of cancer. "Starving cancer" has been pursued to curb tumor progression. An ,intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. In addition, during cancer progression, cancer cells may suffer from insufficient glucose supply. Yet cancer cells can somehow tolerate glucose starvation. Uncovering the underlying mechanisms shall not only shed insight into cancer progression but also benefit cancer therapy. TFE3 is a transcription factor known to activate autophagic genes. Physiological TFE3 activity is regulated by phosphorylation-triggered translocation responsive to nutrient status. We recently reported TFE3 constitutively localizes to the cell nucleus and promotes cell proliferation in kidney cancer even under nutrient replete condition. Whether and how TFE3 responds to glucose starvation remain unclear. In this study, we show TFE3 promotes kidney cancer cell resistance to glucose starvation by exposing cells to physiologically relevant glucose concentration. We find glucose starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through an unbiased functional genomic study, we identify SLC36A1, a lysosomal amino acid transporter, as a TFE3 target gene sensitive to TFE3 protein level. We find SLC36A1 is overexpressed in kidney cancer, which promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is induced by glucose starvation through TFE3, which enhances cellular resistance to glucose starvation. Suppressing TFE3 or SLC36A1 significantly increases cellular sensitivity to GLUT1 inhibitor in kidney cancer cells. Collectively, we uncover a functional TFE3-SLC36A1 axis that responds to glucose starvation and enhances starvation tolerance in kidney cancer.
    Keywords:  O-GlcNAcylation; amino acid transporter; kidney cancer; transcription factor
    DOI:  https://doi.org/10.1016/j.jbc.2024.107270
  44. Nat Commun. 2024 Apr 10. 15(1): 3110
    DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues.
    Kian Hong Kock, Patrick K Kimes, Stephen S Gisselbrecht, Sachi Inukai, Sabrina K Phanor, James T Anderson, Gayatri Ramakrishnan, Colin H Lipper, Dongyuan Song, Jesse V Kurland, Julia M Rogers, Raehoon Jeong, Stephen C Blacklow, Rafael A Irizarry, Martha L Bulyk.
      Homeodomains (HDs) are the second largest class of DNA binding domains (DBDs) among eukaryotic sequence-specific transcription factors (TFs) and are the TF structural class with the largest number of disease-associated mutations in the Human Gene Mutation Database (HGMD). Despite numerous structural studies and large-scale analyses of HD DNA binding specificity, HD-DNA recognition is still not fully understood. Here, we analyze 92 human HD mutants, including disease-associated variants and variants of uncertain significance (VUS), for their effects on DNA binding activity. Many of the variants alter DNA binding affinity and/or specificity. Detailed biochemical analysis and structural modeling identifies 14 previously unknown specificity-determining positions, 5 of which do not contact DNA. The same missense substitution at analogous positions within different HDs often exhibits different effects on DNA binding activity. Variant effect prediction tools perform moderately well in distinguishing variants with altered DNA binding affinity, but poorly in identifying those with altered binding specificity. Our results highlight the need for biochemical assays of TF coding variants and prioritize dozens of variants for further investigations into their pathogenicity and the development of clinical diagnostics and precision therapies.
    DOI:  https://doi.org/10.1038/s41467-024-47396-0
  45. Nat Commun. 2024 Apr 12. 15(1): 3197
    Diverse and abundant phages exploit conjugative plasmids.
    Natalia Quinones-Olvera, Siân V Owen, Lucy M McCully, Maximillian G Marin, Eleanor A Rand, Alice C Fan, Oluremi J Martins Dosumu, Kay Paul, Cleotilde E Sanchez Castaño, Rachel Petherbridge, Jillian S Paull, Michael Baym.
      Phages exert profound evolutionary pressure on bacteria by interacting with receptors on the cell surface to initiate infection. While the majority of phages use chromosomally encoded cell surface structures as receptors, plasmid-dependent phages exploit plasmid-encoded conjugation proteins, making their host range dependent on horizontal transfer of the plasmid. Despite their unique biology and biotechnological significance, only a small number of plasmid-dependent phages have been characterized. Here we systematically search for new plasmid-dependent phages targeting IncP and IncF plasmids using a targeted discovery platform, and find that they are common and abundant in wastewater, and largely unexplored in terms of their genetic diversity. Plasmid-dependent phages are enriched in non-canonical types of phages, and all but one of the 65 phages we isolated were non-tailed, and members of the lipid-containing tectiviruses, ssDNA filamentous phages or ssRNA phages. We show that plasmid-dependent tectiviruses exhibit profound differences in their host range which is associated with variation in the phage holin protein. Despite their relatively high abundance in wastewater, plasmid-dependent tectiviruses are missed by metaviromic analyses, underscoring the continued importance of culture-based phage discovery. Finally, we identify a tailed phage dependent on the IncF plasmid, and find related structural genes in phages that use the orthogonal type 4 pilus as a receptor, highlighting the evolutionarily promiscuous use of these distinct contractile structures by multiple groups of phages. Taken together, these results indicate plasmid-dependent phages play an under-appreciated evolutionary role in constraining horizontal gene transfer via conjugative plasmids.
    DOI:  https://doi.org/10.1038/s41467-024-47416-z
  46. Nat Commun. 2024 Apr 11. 15(1): 3146
    Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
    Trendelina Rrustemi, Katrina Meyer, Yvette Roske, Bora Uyar, Altuna Akalin, Koshi Imami, Yasushi Ishihama, Oliver Daumke, Matthias Selbach.
      Despite their lack of a defined 3D structure, intrinsically disordered regions (IDRs) of proteins play important biological roles. Many IDRs contain short linear motifs (SLiMs) that mediate protein-protein interactions (PPIs), which can be regulated by post-translational modifications like phosphorylation. 20% of pathogenic missense mutations are found in IDRs, and understanding how such mutations affect PPIs is essential for unraveling disease mechanisms. Here, we employ peptide-based interaction proteomics to investigate 36 disease-associated mutations affecting phosphorylation sites. Our results unveil significant differences in interactomes between phosphorylated and non-phosphorylated peptides, often due to disrupted phosphorylation-dependent SLiMs. We focused on a mutation of a serine phosphorylation site in the transcription factor GATAD1, which causes dilated cardiomyopathy. We find that this phosphorylation site mediates interaction with 14-3-3 family proteins. Follow-up experiments reveal the structural basis of this interaction and suggest that 14-3-3 binding affects GATAD1 nucleocytoplasmic transport by masking a nuclear localisation signal. Our results demonstrate that pathogenic mutations of human phosphorylation sites can significantly impact protein-protein interactions, offering insights into potential molecular mechanisms underlying pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-46794-8
  47. Science. 2024 Apr 12. 384(6692): 156-157
    Closing the loop on thermoset plastic recycling.
    Bryce T Nicholls, Brett P Fors.
      A bio-based plastic advances recycling.
    DOI:  https://doi.org/10.1126/science.ado8562
  48. Nat Neurosci. 2024 Apr 09.
    Single-cell long-read sequencing-based mapping reveals specialized splicing patterns in developing and adult mouse and human brain.
    Anoushka Joglekar, Wen Hu, Bei Zhang, Oleksandr Narykov, Mark Diekhans, Jordan Marrocco, Jennifer Balacco, Lishomwa C Ndhlovu, Teresa A Milner, Olivier Fedrigo, Erich D Jarvis, Gloria Sheynkman, Dmitry Korkin, M Elizabeth Ross, Hagen U Tilgner.
      RNA isoforms influence cell identity and function. However, a comprehensive brain isoform map was lacking. We analyze single-cell RNA isoforms across brain regions, cell subtypes, developmental time points and species. For 72% of genes, full-length isoform expression varies along one or more axes. Splicing, transcription start and polyadenylation sites vary strongly between cell types, influence protein architecture and associate with disease-linked variation. Additionally, neurotransmitter transport and synapse turnover genes harbor cell-type variability across anatomical regions. Regulation of cell-type-specific splicing is pronounced in the postnatal day 21-to-postnatal day 28 adolescent transition. Developmental isoform regulation is stronger than regional regulation for the same cell type. Cell-type-specific isoform regulation in mice is mostly maintained in the human hippocampus, allowing extrapolation to the human brain. Conversely, the human brain harbors additional cell-type specificity, suggesting gain-of-function isoforms. Together, this detailed single-cell atlas of full-length isoform regulation across development, anatomical regions and species reveals an unappreciated degree of isoform variability across multiple axes.
    DOI:  https://doi.org/10.1038/s41593-024-01616-4
  49. Nat Neurosci. 2024 Apr;27(4): 606
    Pushing the bounds on dimensionality.
    Luis A Mejia.
      
    DOI:  https://doi.org/10.1038/s41593-024-01623-5
  50. Immunity. 2024 Mar 29. pii: S1074-7613(24)00137-7. [Epub ahead of print]
    Type I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection.
    Lucy Cooper, Hui Xu, Jack Polmear, Liam Kealy, Christopher Szeto, Ee Shan Pang, Mansi Gupta, Alana Kirn, Justin J Taylor, Katherine J L Jackson, Benjamin J Broomfield, Angela Nguyen, Catarina Gago da Graça, Nicole La Gruta, Daniel T Utzschneider, Joanna R Groom, Luciano Martelotto, Ian A Parish, Meredith O'Keeffe, Christopher D Scharer, Stephanie Gras, Kim L Good-Jacobson.
      Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet+ subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c+CD80+ cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.
    Keywords:  B cells; IFN; LCMV; atypical; chronic viral infection; epigenetics; long COVID; memory B cells; scATAC-seq; scRNA-seq
    DOI:  https://doi.org/10.1016/j.immuni.2024.03.016
  51. Nat Cell Biol. 2024 Apr 10.
    Adding a transcription-coupled repair pathway.
    Marco Saponaro.
      
    DOI:  https://doi.org/10.1038/s41556-024-01399-7
  52. Nature. 2024 Apr 10.
    Genetic risk variants lead to type 2 diabetes development through different pathways.
      
    Keywords:  Diabetes; Genetics
    DOI:  https://doi.org/10.1038/d41586-024-00440-x
  53. Nature. 2024 Apr 08.
    How two PhD students overcame the odds to snag tenure-track jobs.
    Violeta Rodriguez, Qimin Liu.
      
    Keywords:  Careers; Lab life; Research management
    DOI:  https://doi.org/10.1038/d41586-024-01047-y
  54. Nat Immunol. 2024 Apr 08.
    MEF2C regulates NK cell effector functions through control of lipid metabolism.
    Joey H Li, Adalia Zhou, Cassidy D Lee, Siya N Shah, Jeong Hyun Ji, Vignesh Senthilkumar, Eddie T Padilla, Andréa B Ball, Qinyan Feng, Christian G Bustillos, Luke Riggan, Alain Greige, Ajit S Divakaruni, Fran Annese, Jessica Cooley-Coleman, Steven A Skinner, Christopher W Cowan, Timothy E O'Sullivan.
      Natural killer (NK) cells are a critical first line of defense against viral infection. Rare mutations in a small subset of transcription factors can result in decreased NK cell numbers and function in humans, with an associated increased susceptibility to viral infection. However, our understanding of the specific transcription factors governing mature human NK cell function is limited. Here we use a non-viral CRISPR-Cas9 knockout screen targeting genes encoding 31 transcription factors differentially expressed during human NK cell development. We identify myocyte enhancer factor 2C (MEF2C) as a master regulator of human NK cell functionality ex vivo. MEF2C-haploinsufficient patients and mice displayed defects in NK cell development and effector function, with an increased susceptibility to viral infection. Mechanistically, MEF2C was required for an interleukin (IL)-2- and IL-15-mediated increase in lipid content through regulation of sterol regulatory element-binding protein (SREBP) pathways. Supplementation with oleic acid restored MEF2C-deficient and MEF2C-haploinsufficient patient NK cell cytotoxic function. Therefore, MEF2C is a critical orchestrator of NK cell antiviral immunity by regulating SREBP-mediated lipid metabolism.
    DOI:  https://doi.org/10.1038/s41590-024-01811-2
  55. Nature. 2024 Apr 10.
    Total solar eclipse 2024: what dazzled scientists.
    Sumeet Kulkarni, Lauren Wolf.
      
    Keywords:  Astronomy and astrophysics; Scientific community; Space physics
    DOI:  https://doi.org/10.1038/d41586-024-01054-z
  56. Nature. 2024 Apr 08.
    How to plug the female mentoring gap in Latin American science.
    Julie Gould.
      
    Keywords:  Careers; Education; Lab life; Society
    DOI:  https://doi.org/10.1038/d41586-024-01024-5
  57. Commun Biol. 2024 Apr 09. 7(1): 432
    A genome-wide association study provides insights into the genetic etiology of 57 essential and non-essential trace elements in humans.
    Marta R Moksnes, Ailin F Hansen, Brooke N Wolford, Laurent F Thomas, Humaira Rasheed, Anica Simić, Laxmi Bhatta, Anne Lise Brantsæter, Ida Surakka, Wei Zhou, Per Magnus, Pål R Njølstad, Ole A Andreassen, Tore Syversen, Jie Zheng, Lars G Fritsche, David M Evans, Nicole M Warrington, Therese H Nøst, Bjørn Olav Åsvold, Trond Peder Flaten, Cristen J Willer, Kristian Hveem, Ben M Brumpton.
      Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study of 57 essential and non-essential trace elements. We perform genome-wide association meta-analyses of 14 trace elements in up to 6564 Scandinavian whole blood samples, and genome-wide association studies of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identify 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide association meta-analyses. In HUNT, several genome-wide significant loci are also indicated for other trace elements. Using two-sample Mendelian randomization, we find several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our current understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health.
    DOI:  https://doi.org/10.1038/s42003-024-06101-z
  58. Nature. 2024 Apr 11.
    This fMRI technique promised to transform brain research - why can no one replicate it?
    McKenzie Prillaman.
      
    Keywords:  Brain; Imaging; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00931-x
  59. Nature. 2024 Apr 10.
    ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D.
    Gang Du, Liam B Healy, Liron David, Caitlin Walker, Tarick J El-Baba, Corinne A Lutomski, Byoungsook Goh, Bowen Gu, Xiong Pi, Pascal Devant, Pietro Fontana, Ying Dong, Xiyu Ma, Rui Miao, Arumugam Balasubramanian, Robbins Puthenveetil, Anirban Banerjee, Hongbo R Luo, Jonathan C Kagan, Sungwhan F Oh, Carol V Robinson, Judy Lieberman, Hao Wu.
      Gasdermin D (GSDMD) is the common effector for cytokine secretion and pyroptosis downstream of inflammasome activation and was previously shown to form large transmembrane pores upon cleavage by inflammatory caspases to generate the GSDMD N-terminal domain (GSDMD-NT)1-10. Here we report that GSDMD Cys191 is S-palmitoylated and palmitoylation is required for pore formation. S-palmitoylation, which does not affect GSDMD cleavage, is augmented by mitochondria-generated reactive oxygen species (ROS). Surprisingly, cleavage-deficient D275A GSDMD is also palmitoylated after inflammasome stimulation or treatment with ROS activators, and causes pyroptosis, although less efficiently than palmitoylated GSDMD-NT. Palmitoylated, but not unpalmitoylated, full-length GSDMD induces liposome leakage, and forms a pore similar in structure to GSDMD-NT pores shown by cryogenic electron microscopy. zDHHC5 and zDHHC9 are the major palmitoyltransferases that mediate GSDMD palmitoylation, and their expression is upregulated by inflammasome activation and ROS. The other human gasdermins are also palmitoylated in their N-termini. These data challenge the concept that cleavage is the only trigger for GSDMD activation. They suggest that reversible palmitoylation is a checkpoint for pore formation by both GSDMD-NT and intact GSDMD that serves as a general switch for the activation of this pore-forming family.
    DOI:  https://doi.org/10.1038/s41586-024-07373-5
  60. Nat Commun. 2024 Apr 11. 15(1): 3140
    Spatiotemporal immune atlas of a clinical-grade gene-edited pig-to-human kidney xenotransplant.
    Matthew D Cheung, Rebecca Asiimwe, Elise N Erman, Christopher F Fucile, Shanrun Liu, Chiao-Wang Sun, Vidya Sagar Hanumanthu, Harish C Pal, Emma D Wright, Gelare Ghajar-Rahimi, Daniel Epstein, Babak J Orandi, Vineeta Kumar, Douglas J Anderson, Morgan E Greene, Markayla Bell, Stefani Yates, Kyle H Moore, Jennifer LaFontaine, John T Killian, Gavin Baker, Jackson Perry, Zayd Khan, Rhiannon Reed, Shawn C Little, Alexander F Rosenberg, James F George, Jayme E Locke, Paige M Porrett.
      Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. Here, we transplant a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and study the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells are uncommon in the porcine kidney cortex early after xenotransplantation and consist of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages express genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft is detectable. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression may be able to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.
    DOI:  https://doi.org/10.1038/s41467-024-47454-7
  61. Nat Commun. 2024 Apr 10. 15(1): 3035
    Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection.
    Leila B Giron, Qin Liu, Opeyemi S Adeniji, Xiangfan Yin, Toshitha Kannan, Jianyi Ding, David Y Lu, Susan Langan, Jinbing Zhang, Joao L L C Azevedo, Shuk Hang Li, Sergei Shalygin, Parastoo Azadi, David B Hanna, Igho Ofotokun, Jason Lazar, Margaret A Fischl, Sabina Haberlen, Bernard Macatangay, Adaora A Adimora, Beth D Jamieson, Charles Rinaldo, Daniel Merenstein, Nadia R Roan, Olaf Kutsch, Stephen Gange, Steven M Wolinsky, Mallory D Witt, Wendy S Post, Andrew Kossenkov, Alan L Landay, Ian Frank, Phyllis C Tien, Robert Gross, Todd T Brown, Mohamed Abdel-Mohsen.
      People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.
    DOI:  https://doi.org/10.1038/s41467-024-47279-4
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