bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–04–13
34 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Neutrophils make matrix to fortify barrier immunity.
  2. FFAR4-mediated IL-6 release from islet macrophages promotes insulin secretion and is compromised in type-2 diabetes.
  3. Brain-wide mapping of immune receptors uncovers a neuromodulatory role of IL-17E and the receptor IL-17RB.
  4. Spatial transcriptomics of the aging mouse brain reveals origins of inflammation in the white matter.
  5. The immune checkpoint regulator CD40 potentiates myocardial inflammation.
  6. CHOIR improves significance-based detection of cell types and states from single-cell data.
  7. GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau.
  8. Common-variant and rare-variant genetic architecture of heart failure across the allele-frequency spectrum.
  9. NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection.
  10. The bridge-like lipid transport protein VPS13C/PARK23 mediates ER-lysosome contacts following lysosome damage.
  11. Multimodal cell maps as a foundation for structural and functional genomics.
  12. The Spatial Transcriptional Activity of Hepatic TCF7L2 Regulates Zonated Metabolic Pathways that Contribute to Liver Fibrosis.
  13. Peripheral neural stem cells from the neural tube contribute to multi-organ neurogenesis.
  14. Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease.
  15. 154 million lives and counting: 5 charts reveal the power of vaccines.
  16. Why it's time the United Nations is led by a woman.
  17. How do I explain the publication gap I ended up with after a hostile manager?
  18. Cells are swapping their mitochondria. What does this mean for our health?
  19. DNA-guided transcription factor interactions extend human gene regulatory code.
  20. The carotenoid torularhodin alleviates NAFLD by promoting Akkermanisa muniniphila-mediated adenosylcobalamin metabolism.
  21. T cells with a taste for tissue remodeling.
  22. Cross-talks between Metabolic and Translational Controls during Beige Adipocyte Differentiation.
  23. The human brainstem's red nucleus was upgraded to support goal-directed action.
  24. Inflammation and disrupted hematopoiesis drive clonal dominance in a mouse model of VEXAS syndrome.
  25. Treg cells augment self-tolerance during infection.
  26. Intergenerational metabolic effects of cold exposure.
  27. Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy.
  28. Chronic stress drives depression by disrupting cellular housekeeping.
  29. Genetics of coronary artery dominance.
  30. Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
  31. Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex.
  32. Myeloid lineage C3 induces reactive gliosis and neuronal stress during CNS inflammation.
  33. RNA G-quadruplexes control mitochondria-localized mRNA translation and energy metabolism.
  34. Suppression of hypothalamic oestrogenic signal sustains hyperprolactinemia and metabolic adaptation in lactating mice.
  1. Nat Rev Immunol. 2025 Apr 09.
    Neutrophils make matrix to fortify barrier immunity.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01170-5
  2. Nat Commun. 2025 Apr 10. 16(1): 3422
    FFAR4-mediated IL-6 release from islet macrophages promotes insulin secretion and is compromised in type-2 diabetes.
    Xinyi Chen, Jingchen Shao, Isabell Brandenburger, Weikun Qian, Lisa Hahnefeld, Rémy Bonnavion, Haaglim Cho, ShengPeng Wang, Juan Hidalgo, Nina Wettschureck, Gerd Geisslinger, Robert Gurke, Zheng Wang, Stefan Offermanns.
      The function of islet macrophages is poorly understood. They promote glucose-stimulated insulin secretion (GSIS) in lean mice, however, the underlying mechanism has remained unclear. We show that activation of the free fatty acid receptor FFAR4 on islet macrophages leads to interleukin-6 (IL-6) release and that IL-6 promotes β-cell function. This mechanism is required for GSIS in lean male mice, but does not function anymore in islets from people with obesity and obese type 2 diabetic male mice. In islets from obese mice, FFAR4 downstream signaling in macrophages is strongly reduced, resulting in impaired FFAR4-mediated IL-6 release. However, IL-6 treatment can still improve GSIS in islets from people with obesity and obese type 2 diabetic mice. These data show that a defect in FFAR4-mediated macrophage activation contributes to reduced GSIS in type 2 diabetes and suggest that reactivating islet macrophage FFAR4 and promoting or mimicking IL-6 release from islet macrophages improves GSIS in type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41467-025-58706-5
  3. Cell. 2025 Apr 03. pii: S0092-8674(25)00279-X. [Epub ahead of print]
    Brain-wide mapping of immune receptors uncovers a neuromodulatory role of IL-17E and the receptor IL-17RB.
    Yunjin Lee, Tomoe Ishikawa, Hyeseung Lee, Byeongjun Lee, Changhyeon Ryu, Irene Davila Mejia, Minjin Kim, Guangqing Lu, Yujin Hong, Mengyang Feng, Hyeyoon Shin, Sylvain Meloche, Richard M Locksley, Ekaterina Koltsova, Sergei I Grivennikov, Myriam Heiman, Gloria B Choi, Jun R Huh.
      Cytokines interact with their receptor complexes to orchestrate diverse processes-from immune responses to behavioral modulation. Interleukin-17A (IL-17A) mediates protective immune responses by binding to IL-17 receptor A (IL-17RA) and IL-17RC subunits. IL-17A also modulates social interaction, yet the role of cytokine receptors in this process and their expression in the brain remains poorly characterized. Here, we mapped the brain-region-specific expression of all major IL-17R subunits and found that in addition to IL-17RA, IL-17RB-but not IL-17RC-plays a role in social behaviors through its expression in the cortex. We further showed that IL-17E, expressed in cortical neurons, enhances social interaction by acting on IL-17RA- and IL-17RB-expressing neurons. These findings highlight an IL-17 circuit within the cortex that modulates social behaviors. Thus, characterizing spatially restricted cytokine receptor expression can be leveraged to elucidate how cytokines function as critical messengers mediating neuroimmune interactions to shape animal behaviors.
    Keywords:  IL-17 receptor; IL-17A; IL-17E (IL-25); IL-17RB; autism; cytokine receptor; social interaction
    DOI:  https://doi.org/10.1016/j.cell.2025.03.006
  4. Nat Commun. 2025 Apr 04. 16(1): 3231
    Spatial transcriptomics of the aging mouse brain reveals origins of inflammation in the white matter.
    Lin Wang, Chang-Yi Cui, Christopher T Lee, Monica Bodogai, Na Yang, Changyou Shi, Mustafa O Irfanoglu, James R Occean, Sadia Afrin, Nishat Sarker, Ross A McDevitt, Elin Lehrmann, Shahroze Abbas, Nirad Banskota, Jinshui Fan, Supriyo De, Peter Rapp, Arya Biragyn, Dan Benjamini, Manolis Maragkakis, Payel Sen.
      To systematically understand age-induced molecular changes, we performed spatial transcriptomics of young, middle-aged, and old mouse brains and identified seven transcriptionally distinct regions. All regions exhibited age-associated upregulation of inflammatory mRNAs and downregulation of mRNAs related to synaptic function. Notably, aging white matter fiber tracts showed the most prominent changes with pronounced effects in females. The inflammatory signatures indicated major ongoing events: microglia activation, astrogliosis, complement activation, and myeloid cell infiltration. Immunofluorescence and quantitative MRI analyses confirmed physical interaction of activated microglia with fiber tracts and concomitant reduction of myelin in old mice. In silico analyses identified potential transcription factors influencing these changes. Our study provides a resourceful dataset of spatially resolved transcriptomic features in the naturally aging murine brain encompassing three age groups and both sexes. The results link previous disjointed findings and provide a comprehensive overview of brain aging identifying fiber tracts as a focal point of inflammation.
    DOI:  https://doi.org/10.1038/s41467-025-58466-2
  5. Nat Cardiovasc Res. 2025 Apr 11.
    The immune checkpoint regulator CD40 potentiates myocardial inflammation.
    Jesus Jimenez, Junedh Amrute, Pan Ma, Xiaoran Wang, Shibali Das, Raymond Dai, Yohei Komaru, Andreas Herrlich, Matthias Mack, Kory J Lavine.
      Immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here we leverage genetic mouse models, single-cell sequencing and cell depletion studies to show that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2+ macrophages and subsequent recruitment of effector memory CD8+ T cells. We identify a positive feedback loop between CCR2+ macrophages (positive for the chemokine receptor CCR2) and CD8+ T cells driven by IL-12b, TNF and IFNγ signaling that promotes myocardial inflammation and show that previous exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates left ventricular remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.
    DOI:  https://doi.org/10.1038/s44161-025-00633-1
  6. Nat Genet. 2025 Apr 07.
    CHOIR improves significance-based detection of cell types and states from single-cell data.
    Cathrine Sant, Lennart Mucke, M Ryan Corces.
      Clustering is a critical step in the analysis of single-cell data, enabling the discovery and characterization of cell types and states. However, most popular clustering tools do not subject results to statistical inference testing, leading to risks of overclustering or underclustering data and often resulting in ineffective identification of cell types with widely differing prevalence. To address these challenges, we present CHOIR (cluster hierarchy optimization by iterative random forests), which applies a framework of random forest classifiers and permutation tests across a hierarchical clustering tree to statistically determine clusters representing distinct populations. We demonstrate the performance of CHOIR through extensive benchmarking against 15 existing clustering methods across 230 simulated and five real single-cell RNA sequencing, assay for transposase-accessible chromatin sequencing, spatial transcriptomic and multi-omic datasets. CHOIR can be applied to any single-cell data type and provides a flexible, scalable and robust solution to the challenge of identifying biologically relevant cell groupings within heterogeneous single-cell data.
    DOI:  https://doi.org/10.1038/s41588-025-02148-8
  7. Nat Commun. 2025 Apr 09. 16(1): 3312
    GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau.
    Diana Acosta Ingram, Emir Turkes, Tae Yeon Kim, Sheeny Vo, Nicholas Sweeney, Marie-Amandine Bonte, Ryan Rutherford, Dominic L Julian, Meixia Pan, Jacob Marsh, Andrea R Argouarch, Min Wu, Douglas W Scharre, Erica H Bell, Lawrence S Honig, Jean Paul Vonsattel, Geidy E Serrano, Thomas G Beach, Celeste M Karch, Aimee W Kao, Mark E Hester, Xianlin Han, Hongjun Fu.
      Lipid dyshomeostasis and tau pathology are present in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). However, the relationship between lipid dyshomeostasis and tau pathology remains unclear. We report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased in excitatory neurons of human neural organoids (HNOs) with the MAPT R406W mutation. Human FTLD, AD cases, and PS19 tau mice also have increased GRAMD1B expression. We show that overexpression of GRAMD1B increases levels of free cholesterol, lipid droplets, and impairs autophagy flux. Modulating GRAMD1B in iPSC-derived neurons also alters key autophagy-related components such as PI3K, phospho-AKT, and p62, as well as phosphorylated tau, and CDK5R1. Blocking GRAMD1B function decreases free cholesterol and lipid droplets. Knocking down GRAMD1B additionally reduces phosphorylated tau, and CDK5R1 expression. Our findings elucidate the role of GRAMD1B in the nervous system and highlight its relevance to FTLD and AD.
    DOI:  https://doi.org/10.1038/s41467-025-58585-w
  8. Nat Genet. 2025 Apr;57(4): 829-838
    Common-variant and rare-variant genetic architecture of heart failure across the allele-frequency spectrum.
    Penn Medicine Biobank
      Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies of all-cause heart failure and examine how different classes of genetic variation impact its heritability. We identify 176 common-variant risk loci at genome-wide significance in 2,358,556 individuals and cluster these signals into five broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity and arrhythmias. In parallel, we uncover exome-wide significant associations for heart failure and rare predicted loss-of-function variants in TTN, MYBPC3, FLNC and BAG3 using exome sequencing of 376,334 individuals. We find that total burden heritability of rare coding variants is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common-variant heritability is diffusely spread throughout the genome. Finally, we show that common-variant background modifies heart failure risk among carriers of rare pathogenic truncating variants in TTN. Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing.
    DOI:  https://doi.org/10.1038/s41588-025-02140-2
  9. Nat Metab. 2025 Apr 11.
    NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection.
    Mia Krapić, Inga Kavazović, Sanja Mikašinović, Karlo Mladenić, Fran Krstanović, Gönül Seyhan, Sabine Helmrath, Elena Camerini, Ilija Brizić, Fleur S Peters, Marc Schmidt-Supprian, Bojan Polić, Tamara Turk Wensveen, Felix M Wensveen.
      The immune system plays a major role in the regulation of adipose tissue homeostasis. Viral infection often drives fat loss, but how and why this happens is unclear. Here, we show that visceral adipose tissue transiently decreases adiposity following viral infection. Upon pathogen encounter, adipose tissue upregulates surface expression of ligands for activating receptors on natural killer cells, which drives IFNγ secretion. This cytokine directly stimulates adipocytes to shift their balance from lipogenesis to lipolysis, which leads to release of lipids in circulation, most notably of free fatty acids. The free fatty acid oleic acid stimulates early-activated B cells by promoting oxidative phosphorylation. Oleic acid promoted expression of co-stimulatory B7 molecules on B cells and promoted their ability to prime CD8+ T cells. Inhibiting lipid uptake by activated B cells impaired CD8+ T cell responses, causing an increase of viral replication in vivo. Our findings uncover a previously unappreciated mechanism of metabolic adaptation to infection and provide a better understanding of the interactions between immune cells and adipose tissue in response to inflammation.
    DOI:  https://doi.org/10.1038/s42255-025-01273-2
  10. Nat Cell Biol. 2025 Apr 10.
    The bridge-like lipid transport protein VPS13C/PARK23 mediates ER-lysosome contacts following lysosome damage.
    Xinbo Wang, Peng Xu, Amanda Bentley-DeSousa, William Hancock-Cerutti, Shujun Cai, Benjamin T Johnson, Francesca Tonelli, Lin Shao, Gabriel Talaia, Dario R Alessi, Shawn M Ferguson, Pietro De Camilli.
      Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease. Here we show that VPS13C, a bridge-like lipid-transport protein and a Parkinson's disease gene, is a sensor of lysosome stress or damage. Following lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an inhibited state of VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. Although another Parkinson's disease protein, LRRK2, is also recruited to stressed or damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery to lysosomes by VPS13C is part of an early protective response to lysosome damage.
    DOI:  https://doi.org/10.1038/s41556-025-01653-6
  11. Nature. 2025 Apr 09.
    Multimodal cell maps as a foundation for structural and functional genomics.
    Leah V Schaffer, Mengzhou Hu, Gege Qian, Kyung-Mee Moon, Abantika Pal, Neelesh Soni, Andrew P Latham, Laura Pontano Vaites, Dorothy Tsai, Nicole M Mattson, Katherine Licon, Robin Bachelder, Anthony Cesnik, Ishan Gaur, Trang Le, William Leineweber, Aji Palar, Ernst Pulido, Yue Qin, Xiaoyu Zhao, Christopher Churas, Joanna Lenkiewicz, Jing Chen, Keiichiro Ono, Dexter Pratt, Peter Zage, Ignacia Echeverria, Andrej Sali, J Wade Harper, Steven P Gygi, Leonard J Foster, Edward L Huttlin, Emma Lundberg, Trey Ideker.
      Human cells consist of a complex hierarchy of components, many of which remain unexplored1,2. Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins in U2OS osteosarcoma cells. Self-supervised multimodal data integration resolves 275 molecular assemblies spanning the range of 10-8 to 10-5 m, which we validate systematically using whole-cell size-exclusion chromatography and annotate using large language models3. We explore key applications in structural biology, yielding structures for 111 heterodimeric complexes and an expanded Rag-Ragulator assembly. The map assigns unexpected functions to 975 proteins, including roles for C18orf21 in RNA processing and DPP9 in interferon signalling, and identifies assemblies with multiple localizations or cell type specificity. It decodes paediatric cancer genomes4, identifying 21 recurrently mutated assemblies and implicating 102 validated new cancer proteins. The associated Cell Visualization Portal and Mapping Toolkit provide a reference platform for structural and functional cell biology.
    DOI:  https://doi.org/10.1038/s41586-025-08878-3
  12. Nat Commun. 2025 Apr 10. 16(1): 3408
    The Spatial Transcriptional Activity of Hepatic TCF7L2 Regulates Zonated Metabolic Pathways that Contribute to Liver Fibrosis.
    Iriscilla Ayala, Skanda K Hebbale, Juho Mononen, Madelaine C Brearley-Sholto, Christopher E Shannon, Ivan Valdez, Marcel Fourcaudot, Terry M Bakewell, Anna Zagorska, Giovanna Romero, Mara Asmis, Fatima A Musa, Jonah T Sily, Annie A Smelter, Edgar A Hinostroza, Leandro C Freitas Lima, Thomas Q de Aguiar Vallim, Sami Heikkinen, Luke Norton.
      The molecular mechanisms regulating the zonal distribution of metabolism in liver are incompletely understood. Here we use single nuclei genomics techniques to examine the spatial transcriptional function of transcription factor 7-like 2 (TCF7L2) in mouse liver, and determine the consequences of TCF7L2 transcriptional inactivation on the metabolic architecture of the liver and the function of zonated metabolic pathways. We report that while Tcf7l2 mRNA expression is ubiquitous across the liver lobule, accessibility of the consensus TCF/LEF DNA binding motif is restricted to pericentral (PC) hepatocytes in zone 3. In mice expressing functionally inactive TCF7L2 in liver, PC hepatocyte-specific gene expression is absent, which we demonstrate promotes hepatic cholesterol accumulation, impaired bile acid synthesis, disruption to glutamine/glutamate homeostasis and pronounced dietary-induced hepatic fibrosis. In summary, TCF7L2 is a key regulator of hepatic zonal gene expression and regulates several zonated metabolic pathways that may contribute to the development of fibrotic liver disease.
    DOI:  https://doi.org/10.1038/s41467-025-58714-5
  13. Nat Cell Biol. 2025 Apr;27(4): 561-562
    Peripheral neural stem cells from the neural tube contribute to multi-organ neurogenesis.
      
    DOI:  https://doi.org/10.1038/s41556-025-01649-2
  14. Nature. 2025 Apr 09.
    Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease.
    Kimitoshi Kimura, Ayshwarya Subramanian, Zhuoran Yin, Ahad Khalilnezhad, Yufan Wu, Danyang He, Karen O Dixon, Udbhav Kasyap Chitta, Xiaokai Ding, Niraj Adhikari, Isabell Guzchenko, Xiaoming Zhang, Ruihan Tang, Thomas Pertel, Samuel A Myers, Aastha Aastha, Masashi Nomura, Ghazaleh Eskandari-Sedighi, Vasundhara Singh, Lei Liu, Conner Lambden, Kilian L Kleemann, Neha Gupta, Jen-Li Barry, Ana Durao, Yiran Cheng, Sebastian Silveira, Huiyuan Zhang, Aamir Suhail, Toni Delorey, Orit Rozenblatt-Rosen, Gordon J Freeman, Dennis J Selkoe, Howard L Weiner, Mathew Blurton-Jones, Carlos Cruchaga, Aviv Regev, Mario L Suvà, Oleg Butovsky, Vijay K Kuchroo.
      Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation1,2. This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer's disease3, and it can induce T cell exhaustion4. However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGFβ signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFβ signalling by promoting TGFBR-mediated SMAD2 phosphorylation, and this process maintains microglial homeostasis. Genetic deletion of Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype (MGnD), also referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-β pathology in 5×FAD mice (a transgenic model of Alzheimer's disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2-deficient 5×FAD mice characterized by increased pro-phagocytic and anti-inflammatory gene expression alongside reduced pro-inflammatory gene expression. These transcriptomic changes were corroborated by single-cell RNA sequencing data across most microglial clusters in Havcr2-deficient 5×FAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGFβ signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41586-025-08852-z
  15. Nature. 2025 Apr 08.
    154 million lives and counting: 5 charts reveal the power of vaccines.
    Heidi Ledford.
      
    Keywords:  Diseases; Public health; Vaccines
    DOI:  https://doi.org/10.1038/d41586-025-00862-1
  16. Nature. 2025 Apr;640(8058): 287-288
    Why it's time the United Nations is led by a woman.
      
    Keywords:  Government; Law; Policy; Politics; Public health
    DOI:  https://doi.org/10.1038/d41586-025-01008-z
  17. Nature. 2025 Apr 09.
    How do I explain the publication gap I ended up with after a hostile manager?
    Bianca Nogrady.
      
    Keywords:  Careers; Lab life; Publishing; Research management
    DOI:  https://doi.org/10.1038/d41586-025-00982-8
  18. Nature. 2025 Apr;640(8058): 302-304
    Cells are swapping their mitochondria. What does this mean for our health?
    Gemma Conroy.
      
    Keywords:  Cancer; Cell biology; Diseases
    DOI:  https://doi.org/10.1038/d41586-025-01064-5
  19. Nature. 2025 Apr 09.
    DNA-guided transcription factor interactions extend human gene regulatory code.
    Zhiyuan Xie, Ilya Sokolov, Maria Osmala, Xue Yue, Grace Bower, J Patrick Pett, Yinan Chen, Kai Wang, Ayse Derya Cavga, Alexander Popov, Sarah A Teichmann, Ekaterina Morgunova, Evgeny Z Kvon, Yimeng Yin, Jussi Taipale.
      In the same way that the mRNA-binding specificities of transfer RNAs define the genetic code, the DNA-binding specificities of transcription factors (TFs) form the molecular basis of the gene regulatory code1,2. The human gene regulatory code is much more complex than the genetic code, in particular because there are more than 1,600 TFs that commonly interact with each other. TF-TF interactions are required for specifying cell fate and executing cell-type-specific transcriptional programs. Despite this, the landscape of interactions between DNA-bound TFs is poorly defined. Here we map the biochemical interactions between DNA-bound TFs using CAP-SELEX, a method that can simultaneously identify individual TF binding preferences, TF-TF interactions and the DNA sequences that are bound by the interacting complexes. A screen of more than 58,000 TF-TF pairs identified 2,198 interacting TF pairs, 1,329 of which preferentially bound to their motifs arranged in a distinct spacing and/or orientation. We also discovered 1,131 TF-TF composite motifs that were markedly different from the motifs of the individual TFs. In total, we estimate that the screen identified between 18% and 47% of all human TF-TF motifs. The novel composite motifs we found were enriched in cell-type-specific elements, active in vivo and more likely to be formed between developmentally co-expressed TFs. Furthermore, TFs that define embryonic axes commonly interacted with different TFs and bound to distinct motifs, explaining how TFs with a similar specificity can define distinct cell types along developmental axes.
    DOI:  https://doi.org/10.1038/s41586-025-08844-z
  20. Nat Commun. 2025 Apr 08. 16(1): 3338
    The carotenoid torularhodin alleviates NAFLD by promoting Akkermanisa muniniphila-mediated adenosylcobalamin metabolism.
    Chang Liu, Xiaojiao Zheng, Jian Ji, Xuan Zhu, Xiaoning Liu, He Liu, Lichun Guo, Kun Ye, Shuang Zhang, Yong-Jiang Xu, Xiulan Sun, Weibiao Zhou, Hoi Leong Xavier Wong, Yaoqi Tian, He Qian.
      Torularhodin, a unique carotenoid, confers beneficial effects on nonalcoholic fatty liver disease (NAFLD). However, the precise mechanism underlying its therapeutic effects remains unknown. Here, we report that torularhodin alleviates NAFLD in male mice by modulating the gut microbiota. Additionally, transplanting fecal microbiota from torularhodin-treated mice to germ-free mice also improves NAFLD. Mechanistically, torularhodin specifically enriches the abundance of Akkermansia muciniphila, which alleviates NAFLD by promoting the synthesis of adenosylcobalamin. Utilizing a human gastrointestinal system and a colonic organoid model, we further demonstrate that adenosylcobalamin confers protective effects against NAFLD through reducing ceramides, a well-known liver damaging compound, and this effect is mediated by inhibition of the hypoxia-inducible factor 2α pathway. Notably, we construct electrospun microsphere-encapsulated torularhodin, which facilitates the slow release of torularhodin in the colon. Together, our findings indicate the therapeutic potential of microbial utilization of carotenoids, such as torularhodin, for treating NAFLD.
    DOI:  https://doi.org/10.1038/s41467-025-58500-3
  21. Immunity. 2025 Apr 08. pii: S1074-7613(25)00131-1. [Epub ahead of print]58(4): 781-783
    T cells with a taste for tissue remodeling.
    Greet Verstichel, Hilde Cheroutre.
      Specialized T cells can support tissue remodeling, but how T cells contribute to mammary gland remodeling during pregnancy is not fully understood. In a recent Cell issue, Corral et al. demonstrate that self-sensing T cells migrate to the mammary gland where they optimize milk production.
    DOI:  https://doi.org/10.1016/j.immuni.2025.03.012
  22. Nat Commun. 2025 Apr 09. 16(1): 3373
    Cross-talks between Metabolic and Translational Controls during Beige Adipocyte Differentiation.
    Daehwa Youn, Boseon Kim, Dahee Jeong, Ju Yeon Lee, Seha Kim, Dulguun Sumberzul, Rehna Paula Ginting, Min-Woo Lee, Ju Hwan Song, Ye Seul Park, Yumin Kim, Chang-Myung Oh, Mihye Lee, Jun Cho.
      Whether and how regulatory events at the translation stage shape the cellular and metabolic features of thermogenic adipocytes is hardly understood. In this study, we report two hitherto unidentified cross-talk pathways between metabolic and translational regulation in beige adipocytes. By analysing temporal profiles of translation activity and protein level changes during precursor-to-beige differentiation, we found selective translational down-regulation of OXPHOS component-coding mRNAs. The down-regulation restricted to Complexes I, III, IV, and V, is coordinated with enhanced translation of TCA cycle genes, engendering distinct stoichiometry of OXPHOS and TCA cycle components and altering the related metabolic activities in mitochondria of thermogenic adipocytes. Our high-resolution description of ribosome positioning unveiled potentiated ribosome pausing at glutamate codons. The increased stalling is attributable to remodelled glutamate metabolism that decreases glutamates for tRNA charging during pan-adipocyte differentiation. The ribosome pauses decrease protein synthesis and mRNA stability of glutamate codon-rich genes, such as actin cytoskeleton-associated genes.
    DOI:  https://doi.org/10.1038/s41467-025-58665-x
  23. Nat Commun. 2025 Apr 10. 16(1): 3398
    The human brainstem's red nucleus was upgraded to support goal-directed action.
    Samuel R Krimmel, Timothy O Laumann, Roselyne J Chauvin, Tamara Hershey, Jarod L Roland, Joshua S Shimony, Jon T Willie, Scott A Norris, Scott Marek, Andrew N Van, Anxu Wang, Julia Monk, Kristen M Scheidter, Forrest I Whiting, Nadeshka Ramirez-Perez, Athanasia Metoki, Noah J Baden, Benjamin P Kay, Joshua S Siegel, Hadas Nahman-Averbuch, Abraham Z Snyder, Damien A Fair, Charles J Lynch, Marcus E Raichle, Evan M Gordon, Nico U F Dosenbach.
      The red nucleus, a large brainstem structure, coordinates limb movement for locomotion in quadrupedal animals. In humans, its pattern of anatomical connectivity differs from that of quadrupeds, suggesting a different purpose. Here, we apply our most advanced resting-state functional connectivity based precision functional mapping in highly sampled individuals (n = 5), resting-state functional connectivity in large group-averaged datasets (combined n ~ 45,000), and task based analysis of reward, motor, and action related contrasts from group-averaged datasets (n > 1000) and meta-analyses (n > 14,000 studies) to precisely examine red nucleus function. Notably, red nucleus functional connectivity with motor-effector networks (somatomotor hand, foot, and mouth) is minimal. Instead, connectivity is strongest to the action-mode and salience networks, which are important for action/cognitive control and reward/motivated behavior. Consistent with this, the red nucleus responds to motor planning more than to actual movement, while also responding to rewards. Our results suggest the human red nucleus implements goal-directed behavior by integrating behavioral valence and action plans instead of serving a pure motor-effector function.
    DOI:  https://doi.org/10.1038/s41467-025-58172-z
  24. Nat Med. 2025 Apr 08.
    Inflammation and disrupted hematopoiesis drive clonal dominance in a mouse model of VEXAS syndrome.
      
    DOI:  https://doi.org/10.1038/s41591-025-03670-2
  25. Nat Immunol. 2025 Apr 10.
    Treg cells augment self-tolerance during infection.
    Ryoji Kawakami, Shimon Sakaguchi.
      
    DOI:  https://doi.org/10.1038/s41590-025-02141-7
  26. Nat Metab. 2025 Apr 07.
    Intergenerational metabolic effects of cold exposure.
    R Teperino.
      
    DOI:  https://doi.org/10.1038/s42255-025-01222-z
  27. Cell Metab. 2025 Apr 02. pii: S1550-4131(25)00106-8. [Epub ahead of print]
    Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy.
    Seyedeh Sahar Mortazavi Farsani, Jignesh Soni, Lu Jin, Anil Kumar Yadav, Shivani Bansal, Tian Mi, Leena Hilakivi-Clarke, Robert Clarke, Benjamin Youngblood, Amrita Cheema, Vivek Verma.
      Mitochondria regulate T cell functions and response to immunotherapy. We show that pyruvate kinase M2 (PKM2) activation enhances mitochondria-dependent effector functions in CD8 and chimeric antigen receptor (CAR)-T cells. Multi-omics and 13C-glucose tracer studies showed that PKM2 agonism alters one-carbon metabolism, decreasing methionine levels, resulting in hypomethylated nuclear and mitochondrial DNA and enhancing mitochondrial biogenesis and functions. PKM2 activation increased the recall responses and anti-tumor functions of CD8 T cells, enhancing adoptive cell therapy. In preclinical models, the PKM2 agonist induced CD8 T cell-dependent anti-tumor responses that synergized with anti-programmed death 1 (PD1) therapy. Immunologically, PKM2 agonists boosted the activation of effector T cells while reducing FoxP3+ T regulatory (Treg) cells in the tumors. The anti-PD1 combination enhanced the frequency of tumor-specific activated CD8 T cells. Together, PKM2 agonism increased mitochondrial functions supporting cell cytotoxicity. Hence, pharmacological targeting of PKM2 can be a clinically viable strategy for enhancement of adoptive cell therapy, in situ anti-tumor immune responses, and immune checkpoint blockade therapy. VIDEO ABSTRACT.
    Keywords:  CD8 T cells; PD1 blockade; PKM2; adoptive cell therapy; immunotherapy; melanoma; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.003
  28. Nature. 2025 Apr 09.
    Chronic stress drives depression by disrupting cellular housekeeping.
    Alberto Corona, Paul J Kenny.
      
    Keywords:  Brain; Depression; Neuroscience; Psychiatric disorders
    DOI:  https://doi.org/10.1038/d41586-025-00910-w
  29. Nat Genet. 2025 Apr;57(4): 774
    Genetics of coronary artery dominance.
    Kyle Vogan.
      
    DOI:  https://doi.org/10.1038/s41588-025-02179-1
  30. Cell Death Dis. 2025 Apr 05. 16(1): 254
    Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
    Ru Deng, Lingyi Fu, Haoyu Liang, Xixiong Ai, Fangyi Liu, Nai Li, Liyan Wu, Shuo Li, Xia Yang, Yansong Lin, Yuhua Huang, Jingping Yun.
      Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-025-07510-6
  31. Nat Commun. 2025 Apr 11. 16(1): 3474
    Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex.
    Zhe Ji, Wing-Yan Skyla Siu, Maria Emilia Dueñas, Leonie Müller, Matthias Trost, Pedro Carvalho.
      Cytokines of the TGF-β superfamily control essential cell fate decisions via receptor regulated SMAD (R-SMAD) transcription factors. Ligand-induced R-SMAD phosphorylation in the cytosol triggers their activation and nuclear accumulation. We determine how R-SMADs are inactivated by dephosphorylation in the cell nucleus to counteract signaling by TGF-β superfamily ligands. We show that R-SMAD dephosphorylation is mediated by an inner nuclear membrane associated complex containing the scaffold protein MAN1 and the CTDNEP1-NEP1R1 phosphatase. Structural prediction, domain mapping and mutagenesis reveals that MAN1 binds independently to the CTDNEP1-NEP1R1 phosphatase and R-SMADs to promote their inactivation by dephosphorylation. Disruption of this complex causes nuclear accumulation of R-SMADs and aberrant signaling, even in the absence of TGF-β ligands. These findings establish CTDNEP1-NEP1R1 as the R-SMAD phosphatase, reveal the mechanistic basis for TGF-β signaling inactivation and highlight how this process is disrupted by disease-associated MAN1 mutations.
    DOI:  https://doi.org/10.1038/s41467-025-58681-x
  32. Nat Commun. 2025 Apr 12. 16(1): 3481
    Myeloid lineage C3 induces reactive gliosis and neuronal stress during CNS inflammation.
    Thomas Garton, Matthew D Smith, Ajay Kesharwani, Marjan Gharagozloo, Sungtaek Oh, Chan-Hyun Na, Martina Absinta, Daniel S Reich, Donald J Zack, Peter A Calabresi.
      Complement component C3 mediates pathology in CNS neurodegenerative diseases. Here we use scRNAseq of sorted C3-reporter positive cells from mouse brain and optic nerve to characterize C3 producing glia in experimental autoimmune encephalomyelitis (EAE), a model in which peripheral immune cells infiltrate the CNS, causing reactive gliosis and neuro-axonal pathology. We find that C3 expression in the early inflammatory stage of EAE defines disease-associated glial subtypes characterized by increased expression of genes associated with mTOR activation and cell metabolism. This pro-inflammatory subtype is abrogated with genetic C3 depletion, a finding confirmed with proteomic analyses. In addition, early optic nerve axonal injury and retinal ganglion cell oxidative stress, but not loss of post-synaptic density protein 95, are ameliorated by selective deletion of C3 in myeloid cells. These data suggest that in addition to C3b opsonization of post synaptic proteins leading to neuronal demise, C3 activation is a contributor to reactive glia in the optic nerve.
    DOI:  https://doi.org/10.1038/s41467-025-58708-3
  33. Nat Commun. 2025 Apr 07. 16(1): 3292
    RNA G-quadruplexes control mitochondria-localized mRNA translation and energy metabolism.
    Leïla Dumas, Sauyeun Shin, Quentin Rigaud, Marie Cargnello, Beatriz Hernández-Suárez, Pauline Herviou, Nathalie Saint-Laurent, Marjorie Leduc, Morgane Le Gall, David Monchaud, Erik Dassi, Anne Cammas, Stefania Millevoi.
      Cancer cells rely on mitochondria for their bioenergetic supply and macromolecule synthesis. Central to mitochondrial function is the regulation of mitochondrial protein synthesis, which primarily depends on the cytoplasmic translation of nuclear-encoded mitochondrial mRNAs whose protein products are imported into mitochondria. Despite the growing evidence that mitochondrial protein synthesis contributes to the onset and progression of cancer, and can thus offer new opportunities for cancer therapy, knowledge of the underlying molecular mechanisms remains limited. Here, we show that RNA G-quadruplexes (RG4s) regulate mitochondrial function by modulating cytoplasmic mRNA translation of nuclear-encoded mitochondrial proteins. Our data support a model whereby the RG4 folding dynamics, under the control of oncogenic signaling and modulated by small molecule ligands or RG4-binding proteins, modifies mitochondria-localized cytoplasmic protein synthesis. Ultimately, this impairs mitochondrial functions, affecting energy metabolism and consequently cancer cell proliferation.
    DOI:  https://doi.org/10.1038/s41467-025-58118-5
  34. Nat Metab. 2025 Apr 10.
    Suppression of hypothalamic oestrogenic signal sustains hyperprolactinemia and metabolic adaptation in lactating mice.
    Meng Yu, Bing Feng, Jonathan C Bean, Qianru Zhao, Yongjie Yang, Hailan Liu, Yongxiang Li, Benjamin P Eappen, Hesong Liu, Longlong Tu, Kristine M Conde, Mengjie Wang, Xi Chen, Na Yin, Darah Ave Threat, Nathan Xu, Junying Han, Peiyu Gao, Yi Zhu, Darryl L Hadsell, Yang He, Pingwen Xu, Yanlin He, Chunmei Wang.
      17β-oestradiol (E2) inhibits overeating and promotes brown adipose tissue (BAT) thermogenesis, whereas prolactin (PRL) does the opposite. During lactation, the simultaneous decline in E2 and surge in PRL contribute to maternal metabolic adaptations, including hyperphagia and suppressed BAT thermogenesis. However, the underlying neuroendocrine mechanisms remain unclear. Here, we find that oestrogen receptor alpha (ERα)-expressing neurons in the medial basal hypothalamus (MBH), specifically the arcuate nucleus of the hypothalamus and the ventrolateral subdivision of the ventromedial hypothalamus (vlVMH), are suppressed during lactation. Deletion of ERα from MBH neurons in virgin female mice induces metabolic phenotypes characteristic of lactation, including hyperprolactinemia, hyperphagia and suppressed BAT thermogenesis. By contrast, activation of ERαvlVMH neurons in lactating mice attenuates these phenotypes. Overall, our study reveals an inhibitory effect of E2-ERαvlVMH signalling on PRL production, which is suppressed during lactation to sustain hyperprolactinemia and metabolic adaptations.
    DOI:  https://doi.org/10.1038/s42255-025-01268-z
This page is being maintained by Thomas Krichel. It was last updated on 2025‒04‒13 at 18:28.