bims-proteo Biomed News
on Proteostasis
Issue of 2023‒08‒27
thirty papers selected by
Eric Chevet, INSERM
  1. LC3 conjugation to lipid droplets.
  2. Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5.
  3. Senescence-specific translation dysregulation desensitizes cells to stress by inhibiting activation of the integrated stress response.
  4. A Zpr1 co-chaperone mediates folding of eukaryotic translation elongation factor 1A via a GTPase cycle.
  5. A strict requirement in proteasome substrates for spacing between ubiquitin tag and degradation initiation elements.
  6. Tumor necrosis factor mediates USE1-independent FAT10ylation under inflammatory conditions.
  7. p62 and NBR1 functions are dispensable for aggrephagy in mouse ESCs and ESC-derived neurons.
  8. MARCH family E3 ubiquitin ligases selectively target and degrade cadherin family proteins.
  9. Membrane localization of LGG-1/GABARAP is dispensable for autophagy in C. elegans.
  10. Targeted Protein Degradation through Recruitment of the CUL4A Complex Adaptor Protein DDB1.
  11. Autophagy is regulated by endoplasmic reticulum calcium homeostasis and sphingolipid metabolism.
  12. A new regulator of autophagy initiation in glia.
  13. Disrupted endoplasmic reticulum-mediated autophagosomal biogenesis in a Drosophila model of C9-ALS-FTD.
  14. Analysis of autophagy deficiency and cytotoxicity in autophagy-deficient human embryonic stem cell-derived neurons.
  15. Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation.
  16. Nix interacts with WIPI2 to induce mitophagy.
  17. The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation.
  18. Structural insights of the p97/VCP AAA+ ATPase: how adapter interactions coordinate diverse cellular functionality.
  19. The deubiquitinase Leon/USP5 interacts with Atg1/ULK1 and antagonizes autophagy.
  20. The ABL-MYC axis controls WIPI1-enhanced autophagy in lifespan extension.
  21. eIF3i promotes colorectal cancer cell survival via augmenting PHGDH translation.
  22. Translation-coupled mRNA quality control mechanisms.
  23. Computational inference of eIF4F complex function and structure in human cancers.
  24. A hierarchical assembly pathway directs the unique subunit arrangement of TRiC/CCT.
  25. The RIDD activity of C. elegans IRE1 modifies neuroendocrine signaling in anticipation of environment stress to ensure survival.
  26. Development of nanoRibo-seq enables study of regulated translation by cortical neuron subtypes, showing uORF translation in synaptic-axonal genes.
  27. PINK1 and Parkin regulate IP3R-mediated ER calcium release.
  28. SARS-CoV-2 nucleocapsid protein inhibits the PKR-mediated integrated stress response through RNA-binding domain N2b.
  29. Synthesis and Evaluation of Cereblon-Recruiting HaloPROTACs.
  30. Impact of PNPLA3 I148M on alpha-1 antitrypsin deficiency-dependent liver disease progression.
  1. Autophagy. 2023 Aug 23. 1-3
    LC3 conjugation to lipid droplets.
    Mohyeddine Omrane, Thomas J Melia, Abdou Rachid Thiam.
      Macroautophagy/autophagy and lipid droplet (LD) biology are intricately linked, with autophagosome-dependent degradation of LDs in response to different signals. LDs play crucial roles in forming autophagosomes possibly by providing essential lipids and serving as a supportive autophagosome assembly platform at the endoplasmic reticulum (ER)-LD interface. LDs and autophagosomes share common proteins, such as VPS13, ATG2, ZFYVE1/DFCP1, and ATG14, but their dual functions remain poorly understood. In our recent study, we found that prolonged starvation leads to ATG3 localizing to large LDs and lipidating LC3B, revealing a non-canonical autophagic role on LDs. In vitro, ATG3 associates with purified and artificial LDs, and conjugated Atg8-family proteins. In long-term starved cells, only LC3B is found on the specific large LDs, positioned near LC3B-positive membranes that undergo lysosome-mediated acidification. This implies that LD-lipidated LC3B acts as a tethering factor, connecting phagophores to LDs and promoting degradation. Our data also support the notion that certain LD surfaces may function as lipidation stations for LC3B, which may move to nearby sites of autophagosome formation. Overall, our study unveils an unknown non-canonical implication of LDs in autophagy processes.Abbreviation: ATG: autophagy-related enzyme, ATP: adenosine triphosphate, E2 enzyme: ubiquitin-conjugating enzyme, ER: endoplasmic reticulum, LD: lipid droplet, LIR motif: LC3-interacting region, MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta, PE: phosphatidylethanolamine, PLIN1: perilipin 1, PNPLA2/ATGL: patatin-like phospholipase domain containing 2, SQSTM1/p62: sequestosome 1, VSP13: vacuolar protein sorting 13, ZFYVE1/DFCP1: zinc finger, FYVE domain containing 1.
    Keywords:  ATG3; LC3B; lipid droplets; membrane contact sites; noncanonical autophagy; prolonged starvation
    DOI:  https://doi.org/10.1080/15548627.2023.2249390
  2. Nat Chem Biol. 2023 Aug 24.
    Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5.
    Laura A Hehl, Daniel Horn-Ghetko, J Rajan Prabu, Ronnald Vollrath, D Tung Vu, David A Pérez Berrocal, Monique P C Mulder, Gerbrand J van der Heden van Noort, Brenda A Schulman.
      Ubiquitin (Ub) chain formation by homologous to E6AP C-terminus (HECT)-family E3 ligases regulates vast biology, yet the structural mechanisms remain unknown. We used chemistry and cryo-electron microscopy (cryo-EM) to visualize stable mimics of the intermediates along K48-linked Ub chain formation by the human E3, UBR5. The structural data reveal a ≈ 620 kDa UBR5 dimer as the functional unit, comprising a scaffold with flexibly tethered Ub-associated (UBA) domains, and elaborately arranged HECT domains. Chains are forged by a UBA domain capturing an acceptor Ub, with its K48 lured into the active site by numerous interactions between the acceptor Ub, manifold UBR5 elements and the donor Ub. The cryo-EM reconstructions allow defining conserved HECT domain conformations catalyzing Ub transfer from E2 to E3 and from E3. Our data show how a full-length E3, ubiquitins to be adjoined, E2 and intermediary products guide a feed-forward HECT domain conformational cycle establishing a highly efficient, broadly targeting, K48-linked Ub chain forging machine.
    DOI:  https://doi.org/10.1038/s41589-023-01414-2
  3. bioRxiv. 2023 Apr 12. pii: 2023.04.12.536613. [Epub ahead of print]
    Senescence-specific translation dysregulation desensitizes cells to stress by inhibiting activation of the integrated stress response.
    Matthew J Payea, Showkat A Dar, Carlos Anerillas, Jennifer L Martindale, Cedric Belair, Rachel Munk, Sulochan Malla, Jinshui Fan, Yulan Piao, Xiaoling Yang, Abid Rehman, Nirad Banskota, Kotb Abdelmohsen, Myriam Gorospe, Manolis Maragkakis.
      Senescence is a state of indefinite cell cycle arrest associated with aging, cancer, and age-related diseases. Here, using label-based mass spectrometry, ribosome profiling and nanopore direct RNA sequencing, we explore the coordinated interaction of translational and transcriptional programs of human cellular senescence. We find that translational deregulation and a corresponding maladaptive integrated stress response (ISR) is a hallmark of senescence that desensitizes senescent cells to stress. We show that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress the stress response transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames. Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. Furthermore, absent a response, stress exacerbates the senescence secretory phenotype and inflammatory pathways thus acting as a possible mechanistic link to disease. Our results reveal a novel mechanism that senescent cells exploit to evade an adaptive stress response and remain viable.
    DOI:  https://doi.org/10.1101/2023.04.12.536613
  4. Mol Cell. 2023 Aug 18. pii: S1097-2765(23)00601-9. [Epub ahead of print]
    A Zpr1 co-chaperone mediates folding of eukaryotic translation elongation factor 1A via a GTPase cycle.
    Alexander J McQuown, Anjali R Nelliat, Dvir Reif, Ibrahim M Sabbarini, Britnie Santiago Membreno, Colin Chih-Chien Wu, Vladimir Denic.
      General protein folding is mediated by chaperones that utilize ATP hydrolysis to regulate client binding and release. Zinc-finger protein 1 (Zpr1) is an essential ATP-independent chaperone dedicated to the biogenesis of eukaryotic translation elongation factor 1A (eEF1A), a highly abundant GTP-binding protein. How Zpr1-mediated folding is regulated to ensure rapid Zpr1 recycling remains an unanswered question. Here, we use yeast genetics and microscopy analysis, biochemical reconstitution, and structural modeling to reveal that folding of eEF1A by Zpr1 requires GTP hydrolysis. Furthermore, we identify the highly conserved altered inheritance of mitochondria 29 (Aim29) protein as a Zpr1 co-chaperone that recognizes eEF1A in the GTP-bound, pre-hydrolysis conformation. This interaction dampens Zpr1⋅eEF1A GTPase activity and facilitates client exit from the folding cycle. Our work reveals that a bespoke ATP-independent chaperone system has mechanistic similarity to ATPase chaperones but unexpectedly relies on client GTP hydrolysis to regulate the chaperone-client interaction.
    Keywords:  chaperones; eEF1A; heat-shock response; integrated stress response; protein folding; protein homeostasis; proteostasis; translation elongation factors
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.028
  5. bioRxiv. 2023 Aug 09. pii: 2023.08.08.552540. [Epub ahead of print]
    A strict requirement in proteasome substrates for spacing between ubiquitin tag and degradation initiation elements.
    Caroline Davis, B L Spaller, Erin Choi, Joseph Kurrasch, Haemin Chong, Suzanne Elsasser, Daniel Finley, Andreas Matouschek.
      Proteins are typically targeted to the proteasome for degradation through the attachment of ubiquitin chains and the proteasome initiates degradation at a disordered region within the target protein. Yet some proteins with ubiquitin chains and disordered regions escape degradation. Here we investigate how the position of the ubiquitin chain on the target protein relative to the disordered region modulates degradation and show that the distance between the two determines whether a protein is degraded efficiently. This distance depends on the type of the degradation tag and is likely a result of the separation on the proteasome between the receptor that binds the tag and the site that engages the disordered region.
    DOI:  https://doi.org/10.1101/2023.08.08.552540
  6. Life Sci Alliance. 2023 Nov;pii: e202301985. [Epub ahead of print]6(11):
    Tumor necrosis factor mediates USE1-independent FAT10ylation under inflammatory conditions.
    Leonie Schnell, Alina Zubrod, Nicola Catone, Johanna Bialas, Annette Aichem.
      The ubiquitin-like modifier FAT10 is up-regulated in many different cell types by IFNγ and TNFα (TNF) and directly targets proteins for proteasomal degradation. FAT10 gets covalently conjugated to its conjugation substrates by the E1 activating enzyme UBA6, the E2 conjugating enzyme USE1, and E3 ligases including Parkin. To date, USE1 was supposed to be the only E2 enzyme for FAT10ylation, and we show here that a knockout of USE1 strongly diminished FAT10 conjugation. Remarkably, under inflammatory conditions in the presence of TNF, FAT10 conjugation appears to be independent of USE1. We report on the identification of additional E2 conjugating enzymes, which were previously not associated with FAT10. We confirm their capacity to be charged with FAT10 onto their active site cysteine, and to rescue FAT10 conjugation in the absence of USE1. This finding strongly widens the field of FAT10 research by pointing to multiple, so far unknown pathways for the conjugation of FAT10, disclosing novel possibilities for pharmacological interventions to regulate FAT10 conjugation under inflammatory conditions and/or viral infections.
    DOI:  https://doi.org/10.26508/lsa.202301985
  7. Life Sci Alliance. 2023 Nov;pii: e202301936. [Epub ahead of print]6(11):
    p62 and NBR1 functions are dispensable for aggrephagy in mouse ESCs and ESC-derived neurons.
    Riccardo Trapannone, Julia Romanov, Sascha Martens.
      Accumulation of protein aggregates is a hallmark of various neurodegenerative diseases. Selective autophagy mediates the delivery of specific cytoplasmic cargo material into lysosomes for degradation. In aggrephagy, which is the selective autophagy of protein aggregates, the cargo receptors p62 and NBR1 were shown to play important roles in cargo selection. They bind ubiquitinated cargo material via their ubiquitin-associated domains and tether it to autophagic membranes via their LC3-interacting regions. We used mouse embryonic stem cells (ESCs) in combination with genome editing to obtain further insights into the roles of p62 and NBR1 in aggrephagy. Unexpectedly, our data reveal that both ESCs and ESC-derived neurons do not show strong defects in the clearance of protein aggregates upon knockout of p62 or NBR1 and upon mutation of the p62 ubiquitin-associated domain and the LC3-interacting region motif. Taken together, our results show a robust aggregate clearance in ESCs and ESC-derived neurons. Thus, redundancy between the cargo receptors, other factors, and pathways, such as the ubiquitin-proteasome system, may compensate for the loss of function of p62 and NBR1.
    DOI:  https://doi.org/10.26508/lsa.202301936
  8. bioRxiv. 2023 Aug 10. pii: 2023.08.10.552739. [Epub ahead of print]
    MARCH family E3 ubiquitin ligases selectively target and degrade cadherin family proteins.
    Tadahiko Seo, Anthony M Lowery, Haifang Xu, William Giang, Sergey M Troyanovsky, Peter A Vincent, Andrew P Kowalczyk.
      Cadherin family proteins play a central role in epithelial and endothelial cell-cell adhesion. The dynamic regulation of cell adhesion is achieved in part through endocytic membrane trafficking pathways that modulate cadherin cell surface levels. Here, we define the role for various MARCH family ubiquitin ligases in the regulation of cadherin degradation. We find that MARCH2 selectively downregulates VE-cadherin, resulting in loss of adherens junction proteins at cell borders and a loss of endothelial barrier function. Interestingly, N-cadherin is refractory to MARCH ligase expression, demonstrating that different classical cadherin family proteins are differentially regulated by MARCH family ligases. Using chimeric cadherins, we find that the specificity of different MARCH family ligases for different cadherins is conferred by the cadherin transmembrane domain. Further, juxta-membrane lysine residues are required for cadherin degradation by MARCH proteins. These findings expand our understanding of cadherin regulation and highlight a new role for mammalian MARCH family ubiquitin ligases in differentially regulating cadherin turnover.
    DOI:  https://doi.org/10.1101/2023.08.10.552739
  9. Autophagy. 2023 Aug 23. 1-2
    Membrane localization of LGG-1/GABARAP is dispensable for autophagy in C. elegans.
    Romane Leboutet, Céline Largeau, Emmanuel Culetto, Christophe Lefebvre, Thorsten Hoppe, Renaud Legouis.
      Most of the functions of LC3/GABARAP in macroautophagy/autophagy are considered to depend on their association with the phagophore membrane through a conjugation to a lipid. Using site-directed mutagenesis, we inhibited the conjugation of LGG-1, the single homolog of GABARAP in C. elegans. Mutants that express only cytosolic forms revealed an essential role for the cleaved form of LGG-1 in autophagy but also in an autophagy-independent embryonic function.
    Keywords:  Atg8; autophagosome biogenesis; conjugation; embryonic development; lipidation; ubiquitin-like
    DOI:  https://doi.org/10.1080/15548627.2023.2249393
  10. bioRxiv. 2023 Aug 12. pii: 2023.08.11.553046. [Epub ahead of print]
    Targeted Protein Degradation through Recruitment of the CUL4A Complex Adaptor Protein DDB1.
    Margot Meyers, Sabine Cismoski, Anoohya Panidapu, Barbara Chie-Leon, Daniel K Nomura.
      Targeted protein degradation has arisen as a powerful therapeutic modality for eliminating proteins. Thus far, most heterobifunctional Proteolysis Targeting Chimeras (PROTACs) have utilized recruiters against substrate receptors of Cullin RING E3 ubiquitin ligases, such as cereblon and VHL. However, previous studies have surprisingly uncovered molecular glue degraders that exploit a CUL4A adaptor protein DDB1 to degrade neosubstrate proteins. Here, we sought to investigate whether DDB1 recruiters can be discovered that can be exploited for PROTAC applications. We utilized activity-based protein profiling and cysteine chemoproteomic screening to identify a covalent recruiter that targets C173 on DDB1 and exploited this recruiter to develop PROTACs against BRD4 and androgen receptor (AR). We demonstrated that the BRD4 PROTAC results in selective degradation of the short BRD4 isoform over the long isoform in a proteasome, NEDDylation, and DDB1-dependent manner. We also demonstrated degradation of AR with the AR PROTAC in prostate cancer cells. Our study demonstrated that covalent chemoproteomic approaches can be used to discover recruiters against Cullin RING adapter proteins and that these recruiters can be used for PROTAC applications to degrade neo-substrates.
    DOI:  https://doi.org/10.1101/2023.08.11.553046
  11. Autophagy. 2023 Aug 23. 1-2
    Autophagy is regulated by endoplasmic reticulum calcium homeostasis and sphingolipid metabolism.
    Shiyan Liu, Mutian Chen, Yichang Wang, Huihui Li, Shiqian Qi, Jia Geng, Kefeng Lu.
      Calcium is involved in a variety of cellular processes. As the crucial components of cell membranes, sphingolipids also play important roles as signaling molecules. Intracellular calcium homeostasis, autophagy initiation and sphingolipid synthesis are associated with the endoplasmic reticulum (ER). Recently, through genetic screening and lipidomics analysis in Saccharomyces cerevisiae, we found that the ER calcium channel Csg2 converts sphingolipid metabolism into macroautophagy/autophagy regulation by controlling ER calcium homeostasis. The results showed that Csg2 acts as a calcium channel to mediate ER calcium efflux into the cytoplasm, and deletion of CSG2 causes a distinct increase of ER calcium concentration, thereby disrupting the stability of the sphingolipid synthase Aur1, leading to the accumulation of the bioactive sphingolipid phytosphingosine (PHS), which specifically and completely blocks autophagy. In summary, our work links calcium homeostasis, sphingolipid metabolism, and autophagy initiation via the ER calcium channel Csg2.
    Keywords:  Autophagosome; Csg2; ER; calcium; sphingolipid; starvation
    DOI:  https://doi.org/10.1080/15548627.2023.2249761
  12. Autophagy. 2023 Aug 24.
    A new regulator of autophagy initiation in glia.
    Linfang Wang, Shiping Zhang, Shuanglong Yi, Margaret S Ho.
      Macroautophagy/autophagy is the major degradation pathway in neurons for eliminating damaged proteins and organelles in Parkinson disease (PD). Like neurons, glial cells are important contributors to PD, yet how autophagy is executed in glia and whether it is using similar interplay as in neurons or other tissues, remain largely elusive. Recently, we reported that the PD risk factor, GAK/aux (cyclin-G-associated kinase/auxilin), regulates the onset of glial autophagy. In the absence of GAK/aux, the number and size of the autophagosomes and autophagosomal precursors increase in adult fly glia and mouse microglia. The protein levels of components in the initiation and class III phosphatidylinositol 3-kinase (PtdIns3K) complexes are generally upregulated. GAK/aux interacts with the master initiation regulator ULK1/Atg1 (unc-51 like autophagy activating kinase 1) via its uncoating domain, hinders autophagy activation by competing with ATG13 (autophagy related 13) for binding to the ULK1 C terminus, and regulates ULK1 trafficking to phagophores. Nonetheless, lack of GAK/aux impairs the autophagic flux and blocks substrate degradation, suggesting that GAK/aux might play additional roles. Overall, our findings reveal a new regulator of autophagy initiation in glia, advancing our understanding on how glia contribute to PD in terms of eliminating pathological protein aggregates.
    Keywords:  GAK/aux; Parkinson’s disease; ULK1/Atg1; autophagy; autophagy initiation; glia
    DOI:  https://doi.org/10.1080/15548627.2023.2251821
  13. Autophagy. 2023 Aug 20.
    Disrupted endoplasmic reticulum-mediated autophagosomal biogenesis in a Drosophila model of C9-ALS-FTD.
    Hyun Sung, Thomas E Lloyd.
      Macroautophagy/autophagy is a major pathway for the clearance of protein aggregates and damaged organelles, and multiple intracellular organelles participate in the process of autophagy, from autophagosome formation to maturation and degradation. Dysregulation of the autophagy pathway has been implicated in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), however the mechanisms underlying autophagy impairment in these diseases are incompletely understood. Since the expansion of GGGGCC (G4C2) repeats in the first intron of the C9orf72 gene is the most common inherited cause of both ALS and FTD (C9-ALS-FTD), we investigated autophagosome dynamics in Drosophila motor neurons expressing 30 G4C2 repeats (30 R). In vivo imaging demonstrates that expression of expanded G4C2 repeats markedly impairs biogenesis of autophagosomes at synaptic termini, whereas trafficking and maturation of axonal autophagosomes are unaffected. Motor neurons expressing 30 R display marked disruption in endoplasmic reticulum (ER) structure and dynamics in the soma, axons, and synapses. Disruption of ER morphology with mutations in Rtnl1 (Reticulon-like 1) or atl (atlastin) also impairs autophagosome formation in motor neurons, suggesting that ER integrity is critical for autophagosome formation. Furthermore, live imaging demonstrates that autophagosomes are generated from dynamic ER tubules at synaptic boutons, and this process fails to occur in a C9-ALS-FTD model. Together, these findings suggest that dynamic ER tubules are required for formation of autophagosomes at the neuromuscular junction, and that this process is disrupted by expanded G4C2 repeats that cause ALS-FTD.
    Keywords:  Autophagy; C9-ALS-FTD; Drosophila; axonal transport; endoplasmic reticulum (ER) dynamics; motor neuron
    DOI:  https://doi.org/10.1080/15548627.2023.2249750
  14. STAR Protoc. 2023 Aug 24. pii: S2666-1667(23)00496-3. [Epub ahead of print]4(3): 102529
    Analysis of autophagy deficiency and cytotoxicity in autophagy-deficient human embryonic stem cell-derived neurons.
    Miriam E Korsgen, Congxin Sun, Elena Seranova, Malgorzata Zatyka, Dewi Astuti, Tetsushi Kataura, Timothy Barrett, Viktor I Korolchuk, Sovan Sarkar.
      Autophagy, a catabolic process governing cellular and energy homeostasis, is essential for cell survival and human health. Here, we present a protocol for generating autophagy-deficient (ATG5-/-) human neurons from human embryonic stem cell (hESC)-derived neural precursors. We describe steps for analyzing loss of autophagy by immunoblotting. We then detail analysis of cell death by luminescence-based cytotoxicity assay and fluorescence-based TUNEL staining. This hESC-based experimental platform provides a genetic knockout model for undertaking autophagy studies relevant to human biology. For complete details on the use and execution of this protocol, please refer to Sun et al. (2023).1.
    Keywords:  Cell Biology; Cell Culture; Cell Differentiation; Cell-Based Assays; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2023.102529
  15. Autophagy. 2023 Aug 24.
    Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation.
    Lisette Van Hove, Annagiada Toniolo, Mohammad Ghiasloo, Kim Lecomte, Fleur Boone, Maarten Ciers, Kris Raaijmakers, Niels Vandamme, Jana Roels, Sophia Maschalidi, Kodi S Ravichandran, Maria Kasper, Geert Van Loo, Esther Hoste.
      Macroautophagy/autophagy is a cellular recycling program regulating cell survival and controlling inflammatory responses in a context-dependent manner. Here, we demonstrate that keratinocyte-selective ablation of Atg16l1, an essential autophagy mediator, results in exacerbated inflammatory and neoplastic skin responses. In addition, mice lacking keratinocyte autophagy exhibit precocious onset of hair follicle growth, indicating altered activation kinetics of hair follicle stem cells (HFSCs). These HFSCs also exhibit expanded potencies in an autophagy-deficient context as shown by de novo hair follicle formation and improved healing of abrasion wounds. ATG16L1-deficient keratinocytes are markedly sensitized to apoptosis. Compound deletion of RIPK3-dependent necroptotic and CASP8-dependent apoptotic responses or of TNFRSF1A/TNFR1 reveals that the enhanced sensitivity of autophagy-deficient keratinocytes to TNF-dependent cell death is driving altered activation of HFSCs. Together, our data demonstrate that keratinocyte autophagy dampens skin inflammation and tumorigenesis but curtails HFSC activation by restraining apoptotic responses.
    Keywords:  Adult stem cell activation; apoptosis; autophagy; hair cycling; hair follicle stem cells; skin cancer; wound healing
    DOI:  https://doi.org/10.1080/15548627.2023.2247742
  16. EMBO J. 2023 Aug 25. e113491
    Nix interacts with WIPI2 to induce mitophagy.
    Eric N Bunker, François Le Guerroué, Chunxin Wang, Marie-Paule Strub, Achim Werner, Nico Tjandra, Richard J Youle.
      Nix is a membrane-anchored outer mitochondrial protein that induces mitophagy. While Nix has an LC3-interacting (LIR) motif that binds to ATG8 proteins, it also contains a minimal essential region (MER) that induces mitophagy through an unknown mechanism. We used chemically induced dimerization (CID) to probe the mechanism of Nix-mediated mitophagy and found that both the LIR and MER are required for robust mitophagy. We find that the Nix MER interacts with the autophagy effector WIPI2 and recruits WIPI2 to mitochondria. The Nix LIR motif is also required for robust mitophagy and converts a homogeneous WIPI2 distribution on the surface of the mitochondria into puncta, even in the absence of ATG8s. Together, this work reveals unanticipated mechanisms in Nix-induced mitophagy and the elusive role of the MER, while also describing an interesting example of autophagy induction that acts downstream of the canonical initiation complexes.
    Keywords:  Autophagy; BNIP3; FIP200; LIR; p62
    DOI:  https://doi.org/10.15252/embj.2023113491
  17. Science. 2023 Aug 25. 381(6660): eadh5021
    The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation.
    Xin Gu, Christopher Nardone, Nolan Kamitaki, Aoyue Mao, Stephen J Elledge, Michael E Greenberg.
      Cells use ubiquitin to mark proteins for proteasomal degradation. Although the proteasome also eliminates proteins that are not ubiquitinated, how this occurs mechanistically is unclear. Here, we found that midnolin promoted the destruction of many nuclear proteins, including transcription factors encoded by the immediate-early genes. Diverse stimuli induced midnolin, and its overexpression was sufficient to cause the degradation of its targets by a mechanism that did not require ubiquitination. Instead, midnolin associated with the proteasome via an α helix, used its Catch domain to bind a region within substrates that can form a β strand, and used a ubiquitin-like domain to promote substrate destruction. Thus, midnolin contains three regions that function in concert to target a large set of nuclear proteins to the proteasome for degradation.
    DOI:  https://doi.org/10.1126/science.adh5021
  18. J Biol Chem. 2023 Aug 21. pii: S0021-9258(23)02210-X. [Epub ahead of print] 105182
    Structural insights of the p97/VCP AAA+ ATPase: how adapter interactions coordinate diverse cellular functionality.
    Julian R Braxton, Daniel R Southworth.
      p97/VCP is an essential eukaryotic AAA+ ATPase with diverse functions including protein homeostasis, membrane remodeling, and chromatin regulation. Dysregulation of p97 function causes severe neurodegenerative disease and is associated with cancer, making this protein a significant therapeutic target. p97 extracts polypeptide substrates from macromolecular assemblies by hydrolysis-driven translocation through its central pore. Growing evidence indicates this activity is highly coordinated by 'adapter' partner proteins, of which more than 30 have been identified and are commonly described to facilitate translocation through substrate recruitment or modification. In so doing, these adapters enable critical p97-dependent functions such as extraction of misfolded proteins from the endoplasmic reticulum or mitochondria, and are likely the reason for the extreme functional diversity of p97 relative to other AAA+ translocases. Here, we review the known functions of adapter proteins and highlight recent structural and biochemical advances that have begun to reveal the diverse molecular bases for adapter-mediated regulation of p97 function. These studies suggest that the range of mechanisms by which p97 activity is controlled is vastly underexplored, with significant advances possible for understanding p97 regulation by most known adapters.
    DOI:  https://doi.org/10.1016/j.jbc.2023.105182
  19. Cell Death Dis. 2023 08 22. 14(8): 540
    The deubiquitinase Leon/USP5 interacts with Atg1/ULK1 and antagonizes autophagy.
    Yueh-Ling Pai, Yuchieh Jay Lin, Wen-Hsin Peng, Li-Ting Huang, He-Yen Chou, Chien-Hsiang Wang, Cheng-Ting Chien, Guang-Chao Chen.
      Accumulating evidence has shown that the quality of proteins must be tightly monitored and controlled to maintain cellular proteostasis. Misfolded proteins and protein aggregates are targeted for degradation through the ubiquitin proteasome (UPS) and autophagy-lysosome systems. The ubiquitination and deubiquitinating enzymes (DUBs) have been reported to play pivotal roles in the regulation of the UPS system. However, the function of DUBs in the regulation of autophagy remain to be elucidated. In this study, we found that knockdown of Leon/USP5 caused a marked increase in the formation of autophagosomes and autophagic flux under well-fed conditions. Genetic analysis revealed that overexpression of Leon suppressed Atg1-induced cell death in Drosophila. Immunoblotting assays further showed a strong interaction between Leon/USP5 and the autophagy initiating kinase Atg1/ULK1. Depletion of Leon/USP5 led to increased levels of Atg1/ULK1. Our findings indicate that Leon/USP5 is an autophagic DUB that interacts with Atg1/ULK1, negatively regulating the autophagic process.
    DOI:  https://doi.org/10.1038/s41419-023-06062-x
  20. Commun Biol. 2023 Aug 24. 6(1): 872
    The ABL-MYC axis controls WIPI1-enhanced autophagy in lifespan extension.
    Katharina Sporbeck, Maximilian L Haas, Carmen J Pastor-Maldonado, David S Schüssele, Catherine Hunter, Zsuzsanna Takacs, Ana L Diogo de Oliveira, Mirita Franz-Wachtel, Chara Charsou, Simon G Pfisterer, Andrea Gubas, Patricia K Haller, Roland L Knorr, Manuel Kaulich, Boris Macek, Eeva-Liisa Eskelinen, Anne Simonsen, Tassula Proikas-Cezanne.
      Human WIPI β-propellers function as PI3P effectors in autophagy, with WIPI4 and WIPI3 being able to link autophagy control by AMPK and TORC1 to the formation of autophagosomes. WIPI1, instead, assists WIPI2 in efficiently recruiting the ATG16L1 complex at the nascent autophagosome, which in turn promotes lipidation of LC3/GABARAP and autophagosome maturation. However, the specific role of WIPI1 and its regulation are unknown. Here, we discovered the ABL-ERK-MYC signalling axis controlling WIPI1. As a result of this signalling, MYC binds to the WIPI1 promoter and represses WIPI1 gene expression. When ABL-ERK-MYC signalling is counteracted, increased WIPI1 gene expression enhances the formation of autophagic membranes capable of migrating through tunnelling nanotubes to neighbouring cells with low autophagic activity. ABL-regulated WIPI1 function is relevant to lifespan control, as ABL deficiency in C. elegans increased gene expression of the WIPI1 orthologue ATG-18 and prolonged lifespan in a manner dependent on ATG-18. We propose that WIPI1 acts as an enhancer of autophagy that is physiologically relevant for regulating the level of autophagic activity over the lifespan.
    DOI:  https://doi.org/10.1038/s42003-023-05236-9
  21. J Biol Chem. 2023 Aug 21. pii: S0021-9258(23)02205-6. [Epub ahead of print] 105177
    eIF3i promotes colorectal cancer cell survival via augmenting PHGDH translation.
    Yaguang Zhang, Xiaowen Wan, Xuyang Yang, Xueqin Liu, Qing Huang, Lian Zhou, Su Zhang, Sicheng Liu, Qunli Xiong, Mingtian Wei, Lei Qiu, Bo Zhang, Junhong Han.
      Translational regulation is one of the decisive steps in gene expression, and its dysregulation is closely related to tumorigenesis. Eukaryotic translation initiation factor 3 subunit i (eIF3i) promotes tumor growth by selectively regulating gene translation, but the underlying mechanisms are largely unknown. Here, we show that eIF3i is significantly increased in colorectal cancer (CRC) and reinforces the proliferation of CRC cells. Using Ribo-seq and proteomics analysis, several genes regulated by eIF3i at the translation level were identified, including D-3-phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme in the de novo serine synthesis pathway that participates in metabolic reprogramming of tumor cells. PHGDH knockdown significantly represses CRC cell proliferation and partially attenuates the excessive growth induced by eIF3i overexpression. Mechanistically, METTL3-mediated m6A modification on PHGDH mRNA promotes its binding with eIF3i, ultimately leading to a higher translational rate. In addition, knocking down eIF3i and PHGDH impedes tumor growth in vivo. Collectively, this study not only uncovered a novel regulatory mechanism for PHGDH translation, but also demonstrated that eIF3i is a critical metabolic regulator in human cancer.
    Keywords:  Colorectal cancer; METTL3; PHGDH; Translational regulation; eIF3i
    DOI:  https://doi.org/10.1016/j.jbc.2023.105177
  22. EMBO J. 2023 Aug 22. e114378
    Translation-coupled mRNA quality control mechanisms.
    Laura Monaghan, Dasa Longman, Javier F Cáceres.
      mRNA surveillance pathways are essential for accurate gene expression and to maintain translation homeostasis, ensuring the production of fully functional proteins. Future insights into mRNA quality control pathways will enable us to understand how cellular mRNA levels are controlled, how defective or unwanted mRNAs can be eliminated, and how dysregulation of these can contribute to human disease. Here we review translation-coupled mRNA quality control mechanisms, including the non-stop and no-go mRNA decay pathways, describing their mechanisms, shared trans-acting factors, and differences. We also describe advances in our understanding of the nonsense-mediated mRNA decay (NMD) pathway, highlighting recent mechanistic findings, the discovery of novel factors, as well as the role of NMD in cellular physiology and its impact on human disease.
    Keywords:  No-go mRNA decay; Non-stop mRNA decay; Nonsense-mediated mRNA decay; RNA quality control; UPF1
    DOI:  https://doi.org/10.15252/embj.2023114378
  23. bioRxiv. 2023 Aug 11. pii: 2023.08.10.552450. [Epub ahead of print]
    Computational inference of eIF4F complex function and structure in human cancers.
    Su Wu, Gerhard Wagner.
      The canonical eukaryotic initiation factor 4F (eIF4F) complex, composed of eIF4G1, eIF4A1, and the cap-binding protein eIF4E, plays a crucial role in cap-dependent translation initiation in eukaryotic cells (1). However, cap-independent initiation can occur through internal ribosomal entry sites (IRESs), involving only eIF4G1 and eIF4A1 present, which is considered to be a complementary process to cap-dependent initiation in tumors under stress conditions (2). The selection and molecular mechanism of specific translation initiation in human cancers remains poorly understood. Thus, we analyzed gene copy number variations (CNVs) in TCGA tumor samples and found frequent amplification of genes involved in translation initiation. Copy number gains in EIF4G1 and EIF3E frequently co-occur across human cancers. Additionally, EIF4G1 expression strongly correlates with genes from cancer cell survival pathways including cell cycle and lipogenesis, in tumors with EIF4G1 amplification or duplication. Furthermore, we revealed that eIF4G1 and eIF4A1 protein levels strongly co-regulate with ribosomal subunits, eIF2, and eIF3 complexes, while eIF4E co-regulates with 4E-BP1, ubiquitination, and ESCRT proteins. Using Alphafold predictions, we modeled the eIF4F structure with and without eIF4G1-eIF4E binding. The modeling for cap-dependent initiation suggests that eIF4G1 interacts with eIF4E through its N-terminal eIF4E-binding domain, bringing eIF4E near the eIF4A1 mRNA binding cavity and closing the cavity with both eIF4G1 HEAT-2 domain and eIF4E. In the cap-independent mechanism, α-helix 5 of eIF4G1 HEAT-2 domain instead directly interacts with the eIF4A1 N-terminal domain to close the mRNA binding cavity without eIF4E involvement, resulting in a stronger interaction between eIF4G1 and eIF4A1.Significance Statement: Translation initiation is primarily governed by eIF4F, employing a "cap-dependent" mechanism, but eIF4F dysregulation may lead to a "cap-independent" mechanism in stressed cancer cells. We found frequent amplification of translation initiation genes, and co-occurring copy number gains of EIF4G1 and EIF3E genes in human cancers. EIF4G1 amplification or duplication may be positively selected for its beneficial impact on the overexpression of cancer survival genes. The co-regulation of eIF4G1 and eIF4A1, distinctly from eIF4E, reveals eIF4F dysregulation favoring cap-independent initiation. Alphafold predicts changes in the eIF4F complex assembly to accommodate both initiation mechanisms. These findings have significant implications for evaluating cancer cell vulnerability to eIF4F inhibition and developing treatments that target cancer cells with dependency on the translation initiation mechanism.
    DOI:  https://doi.org/10.1101/2023.08.10.552450
  24. Mol Cell. 2023 Aug 18. pii: S1097-2765(23)00606-8. [Epub ahead of print]
    A hierarchical assembly pathway directs the unique subunit arrangement of TRiC/CCT.
    Karen Betancourt Moreira, Miranda P Collier, Alexander Leitner, Kathy H Li, Ivana L Serrano Lachapel, Frank McCarthy, Kwadwo A Opoku-Nsiah, Fabián Morales-Polanco, Natália Barbosa, Daniel Gestaut, Rahul S Samant, Soung-Hun Roh, Judith Frydman.
      How the essential eukaryotic chaperonin TRiC/CCT assembles from eight distinct subunits into a unique double-ring architecture remains undefined. We show TRiC assembly involves a hierarchical pathway that segregates subunits with distinct functional properties until holocomplex (HC) completion. A stable, likely early intermediate arises from small oligomers containing CCT2, CCT4, CCT5, and CCT7, contiguous subunits that constitute the negatively charged hemisphere of the TRiC chamber, which has weak affinity for unfolded actin. The remaining subunits CCT8, CCT1, CCT3, and CCT6, which comprise the positively charged chamber hemisphere that binds unfolded actin more strongly, join the ring individually. Unincorporated late-assembling subunits are highly labile in cells, which prevents their accumulation and premature substrate binding. Recapitulation of assembly in a recombinant system demonstrates that the subunits in each hemisphere readily form stable, noncanonical TRiC-like HCs with aberrant functional properties. Thus, regulation of TRiC assembly along a biochemical axis disfavors the formation of stable alternative chaperonin complexes.
    Keywords:  TRiC/CCT; actin folding; assembly intermediates; chaperonin; complex assembly; orphan subunits; protein folding
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.031
  25. bioRxiv. 2023 Aug 15. pii: 2023.08.10.552841. [Epub ahead of print]
    The RIDD activity of C. elegans IRE1 modifies neuroendocrine signaling in anticipation of environment stress to ensure survival.
    Mingjie Ying, Yair Argon, Tali Gidalevitz.
      Xbp1 splicing and regulated IRE1-dependent RNA decay (RIDD) are two RNase activities of the ER stress sensor IRE1. While Xbp1 splicing has important roles in stress responses and animal physiology, the physiological role(s) of RIDD remain enigmatic. Genetic evidence in C. elegans connects XBP1-independent IRE1 activity to organismal stress adaptation, but whether this is via RIDD, and what are the targets is yet unknown. We show that cytosolic kinase/RNase domain of C. elegans IRE1 is indeed capable of RIDD in human cells, and that sensory neurons use RIDD to signal environmental stress, by degrading mRNA of TGFβ-like growth factor DAF-7. daf-7 was degraded in human cells by both human and worm IRE1 RNAse activity with same efficiency and specificity as Blos1, confirming daf-7 as RIDD substrate. Surprisingly, daf-7 degradation in vivo was triggered by concentrations of ER stressor tunicamycin too low for xbp-1 splicing. Decrease in DAF-7 normally signals food limitation and harsh environment, triggering adaptive changes to promote population survival. Because C. elegans is a bacteriovore, and tunicamycin, like other common ER stressors, is an antibiotic secreted by Streptomyces spp. , we asked whether daf-7 degradation by RIDD could signal pending food deprivation. Indeed, pre-emptive tunicamycin exposure increased survival of C. elegans populations under food limiting/high temperature stress, and this protection was abrogated by overexpression of DAF-7. Thus, C. elegans uses stress-inducing metabolites in its environment as danger signals, and employs IRE1's RIDD activity to modulate the neuroendocrine signaling for survival of upcoming environmental challenge.
    DOI:  https://doi.org/10.1101/2023.08.10.552841
  26. Cell Rep. 2023 Aug 24. pii: S2211-1247(23)01006-9. [Epub ahead of print]42(9): 112995
    Development of nanoRibo-seq enables study of regulated translation by cortical neuron subtypes, showing uORF translation in synaptic-axonal genes.
    John E Froberg, Omer Durak, Jeffrey D Macklis.
      Investigation of translation in rare cell types or subcellular contexts is challenging due to large input requirements for standard approaches. Here, we present "nanoRibo-seq" an optimized approach using 102- to 103-fold less input material than bulk approaches. nanoRibo-seq exhibits rigorous quality control features consistent with quantification of ribosome protected fragments with as few as 1,000 cells. We compare translatomes of two closely related cortical neuron subtypes, callosal projection neurons (CPN) and subcerebral projection neurons (SCPN), during their early postnatal development. We find that, while translational efficiency is highly correlated between CPN and SCPN, several dozen mRNAs are differentially translated. We further examine upstream open reading frame (uORF) translation and identify that mRNAs involved in synapse organization and axon development are highly enriched for uORF translation in both subtypes. nanoRibo-seq enables investigation of translational regulation of rare cell types in vivo and offers a flexible approach for globally quantifying translation from limited input material.
    Keywords:  CP: Neuroscience; Ribo-seq; callosal projection neurons; cortical development; mRNA translation; molecular controls over neuronal diversity; ribosome; ribosome profiling; subcerebral projection neurons; translational regulation; upstream open reading frame (uORF)
    DOI:  https://doi.org/10.1016/j.celrep.2023.112995
  27. Nat Commun. 2023 Aug 25. 14(1): 5202
    PINK1 and Parkin regulate IP3R-mediated ER calcium release.
    Su Jin Ham, Heesuk Yoo, Daihn Woo, Da Hyun Lee, Kyu-Sang Park, Jongkyeong Chung.
      Although defects in intracellular calcium homeostasis are known to play a role in the pathogenesis of Parkinson's disease (PD), the underlying molecular mechanisms remain unclear. Here, we show that loss of PTEN-induced kinase 1 (PINK1) and Parkin leads to dysregulation of inositol 1,4,5-trisphosphate receptor (IP3R) activity, robustly increasing ER calcium release. In addition, we identify that CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) functions downstream of Parkin to directly control IP3R. Both genetic and pharmacologic suppression of CISD1 and its Drosophila homolog CISD (also known as Dosmit) restore the increased ER calcium release in PINK1 and Parkin null mammalian cells and flies, respectively, demonstrating the evolutionarily conserved regulatory mechanism of intracellular calcium homeostasis by the PINK1-Parkin pathway. More importantly, suppression of CISD in PINK1 and Parkin null flies rescues PD-related phenotypes including defective locomotor activity and dopaminergic neuronal degeneration. Based on these data, we propose that the regulation of ER calcium release by PINK1 and Parkin through CISD1 and IP3R is a feasible target for treating PD pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-023-40929-z
  28. PLoS Pathog. 2023 Aug 22. 19(8): e1011582
    SARS-CoV-2 nucleocapsid protein inhibits the PKR-mediated integrated stress response through RNA-binding domain N2b.
    Chiara Aloise, Jelle G Schipper, Arno van Vliet, Judith Oymans, Tim Donselaar, Daniel L Hurdiss, Raoul J de Groot, Frank J M van Kuppeveld.
      The nucleocapsid protein N of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enwraps and condenses the viral genome for packaging but is also an antagonist of the innate antiviral defense. It suppresses the integrated stress response (ISR), purportedly by interacting with stress granule (SG) assembly factors G3BP1 and 2, and inhibits type I interferon responses. To elucidate its mode of action, we systematically deleted and over-expressed distinct regions and domains. We show that N via domain N2b blocks PKR-mediated ISR activation, as measured by suppression of ISR-induced translational arrest and SG formation. N2b mutations that prevent dsRNA binding abrogate these activities also when introduced in the intact N protein. Substitutions reported to block post-translation modifications of N or its interaction with G3BP1/2 did not have a detectable additive effect. In an encephalomyocarditis virus-based infection model, N2b - but not a derivative defective in RNA binding-prevented PKR activation, inhibited β-interferon expression and promoted virus replication. Apparently, SARS-CoV-2 N inhibits innate immunity by sequestering dsRNA to prevent activation of PKR and RIG-I-like receptors. Similar observations were made for the N protein of human coronavirus 229E, suggesting that this may be a general trait conserved among members of other orthocoronavirus (sub)genera.
    DOI:  https://doi.org/10.1371/journal.ppat.1011582
  29. Chembiochem. 2023 Aug 25. e202300498
    Synthesis and Evaluation of Cereblon-Recruiting HaloPROTACs.
    Britton K Ody, Jing Zhang, Sydney E Nelson, Yayun Xie, Ruochuan Liu, Cayden J Dodd, Savannah E Jacobs, Savannah L Whitzel, Leighan A Williams, Samer Gozem, Mark Turlington, Jun Yin.
      Target validation is key to the development of protein degrading molecules such as proteolysis-targeting chimeras (PROTACs) to identify cellular proteins amenable for induced degradation by the ubiquitin-proteasome system (UPS). Previously the HaloPROTAC system was developed to screen targets of PROTACs by linking the chlorohexyl group with the ligands of E3 ubiquitin ligases VHL and cIAP1 to recruit target proteins fused to the HaloTag for E3-catalyzed ubiquitination. Reported here are HaloPROTACs that engage the cereblon (CRBN) E3 to ubiquitinate and degrade HaloTagged proteins. A focused library of CRBN-pairing HaloPROTACs was synthesized and screened to identify efficient degraders of EGFP-HaloTag fusion with higher activities than VHL-engaging HaloPROTACs at sub-micromolar concentrations of the compound. The CRBN-engaging HaloPROTACs broadens the scope of the E3 ubiquitin ligases that can be utilized to screen suitable targets for induced protein degradation in the cell.
    Keywords:  PROTAC · HaloTag · HaloPROTAC · ubiquitin · Cereblon
    DOI:  https://doi.org/10.1002/cbic.202300498
  30. Hepatology. 2023 Aug 25.
    Impact of PNPLA3 I148M on alpha-1 antitrypsin deficiency-dependent liver disease progression.
    Ines Volkert, Malin Fromme, Carolin Schneider, Lena Candels, Cecilia Lindhauer, Huan Su, Katrine Thorhauge, Monica Pons, Mohamed Ramadan Mohamed, Kai Markus Schneider, Pavel Strnad, Christian Trautwein.
      BACKGROUND AND AIMS: Genetic risk factors are major determinants of chronic liver disease (CDL) progression. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M polymorphism and alpha-1 antitrypsin E342K variant, termed PiZ, are major modifiers of metabolic CLD. Both variants are known to affect metabolic CLD via increased endoplasmic reticulum stress, but their combined effect on CLD progression remains largely unknown. Here we aimed to test our working hypothesis that their combined incidence triggers CLD disease progression.APPROACH AND RESULTS: We showed that PiZZ/PNPLA3I148M patients from the European AATD liver consortium and UK Biobank had a trend towards higher liver enzymes, but no increased liver fat accumulation was evident between subgroups. After generating transgenic mice that overexpress the PiZ variant and simultaneously harbor the PNPLA3I148M knockin (designated as PiZ/PNPLA3I148M), we observed that PiZ and PiZ/PNPLA3I148M animals showed increased liver enzymes compared to controls during aging. However, no significant difference between PiZ and PiZ/PNPLA3I148M groups was observed with no increased liver fat accumulation over time. To further study the impact on CLD progression a Western-Styled diet (WSD) was administered, which resulted in increased fat accumulation and fibrosis in PiZ and PiZ/PNPLA3I148M livers compared to controls, but the additional presence of PNPLA3I148M had no impact on liver phenotype. Notably, PiZ variant protected PNPLA3I148M mice from liver damage and obesity after WSD feeding.
    CONCLUSION: Our results demonstrate that the PNPLA3 polymorphism in the absence of additional metabolic risk factors is insufficient to drive the development of advanced liver disease in severe alpha1-antitrypsin deficiency.
    DOI:  https://doi.org/10.1097/HEP.0000000000000574
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