bims-proteo Biomed News
on Proteostasis
Issue of 2022‒10‒16
29 papers selected by
Eric Chevet
INSERM
  1. RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy.
  2. Defective Human SRP Induces Protein Quality Control and Triggers Stress Response.
  3. SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer.
  4. Global ubiquitinome analysis reveals the role of E3 ubiquitin ligase FaBRIZ in strawberry fruit ripening.
  5. Comparative proteomics reveals elevated CCN2 in NGLY1-deficient cells.
  6. Lipid and protein content profiling of isolated native autophagic vesicles.
  7. Disulfide Bond Formation and Redox Regulation in the Golgi Apparatus.
  8. Endoplasmic Reticulum Homeostasis Regulates TLR4 Expression and Signaling in Mast Cells.
  9. Novel insights into the non-canonical roles of PSMD14/POH1/Rpn11 in proteostasis and in the modulation of cancer progression.
  10. Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation.
  11. Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition.
  12. Convergence of secretory, endosomal, and autophagic routes in trans-Golgi-associated lysosomes.
  13. IRE1α-XBP1 regulates PDK1-dependent induction of epithelial-mesenchymal transition in non-small cell lung cancer cells.
  14. Genetic deletion of hspa8 leads to selective tissue malformations in zebrafish embryonic development.
  15. An unusual mode of baseline translation adjusts cellular protein synthesis capacity to metabolic needs.
  16. Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection.
  17. The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α.
  18. BNIP3L/NIX regulates both mitophagy and pexophagy.
  19. Membrane-assisted assembly and selective secretory autophagy of enteroviruses.
  20. The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS.
  21. A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.
  22. KIRA8 attenuates non-alcoholic steatohepatitis through inhibition of the IRE1α/XBP1 signalling pathway.
  23. Predicting the structure of large protein complexes using AlphaFold and Monte Carlo tree search.
  24. Synthesis of O-GlcNAcylated small heat shock proteins.
  25. Emerging degrader technologies engaging lysosomal pathways.
  26. The Autophagy Receptor TAX1BP1 (T6BP) improves antigen presentation by MHC-II molecules.
  27. Discovery of Potent OTUB1/USP8 Dual Inhibitors Targeting Proteostasis in Non-Small-Cell Lung Cancer.
  28. Proximity proteomics of synaptopodin provides insight into the molecular composition of the spine apparatus of dendritic spines.
  29. Dysfunctional tRNA reprogramming and codon-biased translation in cancer.
  1. Nat Commun. 2022 Oct 12. 13(1): 6007
    RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy.
    Jing Zhang, Bin Wang, Xiaoxiao Gao, Cheng Peng, Chao Shan, Silas F Johnson, Richard C Schwartz, Yong-Hui Zheng.
      Virus infection affects cellular proteostasis and provides an opportunity to study this cellular process under perturbation. The proteostasis network in the endoplasmic reticulum (ER) is composed of the calnexin cycle, and the two protein degradation pathways ER-associated protein degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD/ER-phagy/reticulophagy). Here we show that calnexin and calreticulin trigger Zaire Ebolavirus (EBOV) glycoprotein GP1,2 misfolding. Misfolded EBOV-GP1,2 is targeted by ERAD machinery, but this results in lysosomal instead of proteasomal degradation. Moreover, the ER Ub ligase RNF185, usually associated with ERAD, polyubiquitinates EBOV-GP1,2 on lysine 673 via ubiquitin K27-linkage. Polyubiquinated GP1,2 is subsequently recruited into autophagosomes by the soluble autophagy receptor sequestosome 1 (SQSTM1/p62), in an ATG3- and ATG5-dependent manner. We conclude that EBOV hijacks all three proteostasis mechanisms in the ER to downregulate GP1,2 via polyubiquitination and show that this increases viral fitness. This study identifies linkages among proteostasis network components previously thought to function independently.
    DOI:  https://doi.org/10.1038/s41467-022-33805-9
  2. J Mol Biol. 2022 Sep 19. pii: S0022-2836(22)00452-1. [Epub ahead of print]434(22): 167832
    Defective Human SRP Induces Protein Quality Control and Triggers Stress Response.
    Elena B Tikhonova, Sneider Alexander Gutierrez Guarnizo, Morgana K Kellogg, Alexander Karamyshev, Igor M Dozmorov, Zemfira N Karamysheva, Andrey L Karamyshev.
      Regulation of Aberrant Protein Production (RAPP) is a protein quality control in mammalian cells. RAPP degrades mRNAs of nascent proteins not able to associate with their natural interacting partners during synthesis at the ribosome. However, little is known about the molecular mechanism of the pathway, its substrates, or its specificity. The Signal Recognition Particle (SRP) is the first interacting partner for secretory proteins. It recognizes signal sequences of the nascent polypeptides when they are exposed from the ribosomal exit tunnel. Here, we reveal the generality of the RAPP pathway on the whole transcriptome level through depletion of human SRP54, an SRP subunit. This depletion triggers RAPP and leads to decreased expression of the mRNAs encoding a number of secretory and membrane proteins. The loss of SRP54 also leads to the dramatic upregulation of a specific network of HSP70/40/90 chaperones (HSPA1A, DNAJB1, HSP90AA1, and others), increased ribosome associated ubiquitination, and change in expression of RPS27 and RPS27L suggesting ribosome rearrangement. These results demonstrate the complex nature of defects in protein trafficking, mRNA and protein quality control, and provide better understanding of their mechanisms at the ribosome.
    Keywords:  protein synthesis and transport; secretory proteins; signal Recognition particle; signal sequence; translational control
    DOI:  https://doi.org/10.1016/j.jmb.2022.167832
  3. iScience. 2022 Oct 21. 25(10): 105183
    SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer.
    Asmita Bhattacharya, Juncheng Wei, Wenxin Song, Beixue Gao, Chunyan Tian, Shuangcheng Alivia Wu, Jian Wang, Ligong Chen, Deyu Fang, Ling Qi.
      Endoplasmic reticulum (ER) homeostasis has been implicated in the pathogenesis of various forms of cancer; however, our understanding of the role of ER quality control mechanisms in tumorigenesis remains incomplete. Here, we show that the SEL1L-HRD1 complex of ER-associated degradation (ERAD) suppresses hepatocyte proliferation and tumorigenesis in mice. Hepatocyte-specific deletion of Sel1L or Hrd1 predisposed mice to diet/chemical-induced tumors. Proteomics screen from SEL1L-deficient livers revealed WNT5A, a tumor suppressor, as an ERAD substrate. Indeed, nascent WNT5A was misfolding prone and degraded by SEL1L-HRD1 ERAD in a quality control capacity. In the absence of ERAD, WNT5A misfolds is largely retained in the ER and forms high-molecular weight aggregates, thereby depicting a loss-of-function effect and attenuating WNT5A-mediated suppression of hepatocyte proliferation. In humans, SEL1L-HRD1 ERAD expression correlated positively with survival time for patients with liver cancer. Overall, our data reveal a key role of SEL1L-HRD1 ERAD in suppressing hepatocyte proliferation and liver cancer.
    Keywords:  Cancer; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105183
  4. J Exp Bot. 2022 Oct 10. pii: erac400. [Epub ahead of print]
    Global ubiquitinome analysis reveals the role of E3 ubiquitin ligase FaBRIZ in strawberry fruit ripening.
    Yuying Wang, Lingxi Kong, Weihao Wang, Guozheng Qin.
      Ubiquitination is an important post-translational modification that mediates protein degradation in eukaryotic cell, participating in multiple biological processes. However, the profiling of protein ubiquitination and the function of this crucial modification in fruit ripening remain largely unknown. In this study, we found that suppression of proteasome by the inhibitor MG132 retarded strawberry fruit ripening. By using K-ɛ-GG antibody enrichment combined with high-resolution mass spectrometry, we performed a comprehensive ubiquitinome analysis in strawberry fruit. We identified 2947 ubiquitination sites for 2878 peptides within 1487 proteins, which are involved in a variety of cellular functions. The lysine at position 48 (K48)-linked poly-ubiquitin chains appeared to be the most prevalent types of modification among the identified ubiquitinated proteins. A large number of ubiquitination sites exhibited altered ubiquitination levels after proteasome inhibition, including those within ripening-related proteins associated with sugar and acid metabolism, cell wall metabolism, anthocyanin synthesis, and ABA biosynthesis and signaling. We further demonstrated that FaBRIZ, a RING-type E3 ligase, functions as a negative regulator of ripening in strawberry fruit. Our findings highlight the critical regulatory roles of protein ubiquitination in fruit ripening. The ubiquitinome data provide a basis for further exploration of the function of ubiquitination on specific proteins.
    Keywords:  fruit ripening; protein post-translational modification; strawberry; ubiquitin-proteasome system (UPS); ubiquitination; ubiquitinome
    DOI:  https://doi.org/10.1093/jxb/erac400
  5. Biochem Biophys Res Commun. 2022 Oct 02. pii: S0006-291X(22)01362-6. [Epub ahead of print]632 165-172
    Comparative proteomics reveals elevated CCN2 in NGLY1-deficient cells.
    Rebecca Hetz, Carlo Magaway, Jaylene Everett, Ling Li, Belinda B Willard, Hudson H Freeze, Ping He.
      N-glycanase 1(NGLY1) catalyzes the removal of N-linked glycans from newly synthesized or misfolded protein. NGLY1 deficiency is a recently diagnosed rare genetic disorder. The affected individuals present a broad spectrum of clinical features. Recent studies explored several possible molecular mechanisms of NGLY1 deficiency including defects in proteostasis, mitochondrial homeostasis, innate immunity, and water/ion transport. We demonstrate abnormal accumulation of endoplasmic reticulum-associated degradation (ERAD) substrates in NGLY1-deficient cells. Global quantitative proteomics discovered elevated levels of endogenous proteins in NGLY1-defective human and mouse cells. Further biological validation assays confirmed the altered abundance of several key candidates that were subjected to isobarically labeled proteomic analysis. CCN2 was selected for further analysis due to its significant increase in different cell models of NGLY1 deficiency. Functional assays show elevated CCN2 and over-stimulated TGF-β signaling in NGLY1-deficient cells. Given the important role of CCN2 and TGF-β pathway in mediating systemic fibrosis, we propose a potential link of increased CCN2 and TGF-β signaling to microscopic liver fibrosis in NGLY1 patients.
    Keywords:  CCN2; Fibrosis; NGLY1; Proteomics; TGF-β signaling
    DOI:  https://doi.org/10.1016/j.bbrc.2022.09.100
  6. EMBO Rep. 2022 Oct 10. e53065
    Lipid and protein content profiling of isolated native autophagic vesicles.
    Daniel Schmitt, Süleyman Bozkurt, Pascale Henning-Domres, Heike Huesmann, Stefan Eimer, Laura Bindila, Christian Behrends, Emily Boyle, Florian Wilfling, Georg Tascher, Christian Münch, Christian Behl, Andreas Kern.
      Autophagy is responsible for clearance of an extensive portfolio of cargoes, which are sequestered into vesicles, called autophagosomes, and are delivered to lysosomes for degradation. The pathway is highly dynamic and responsive to several stress conditions. However, the phospholipid composition and protein contents of human autophagosomes under changing autophagy rates are elusive so far. Here, we introduce an antibody-based FACS-mediated approach for the isolation of native autophagic vesicles and ensured the quality of the preparations. Employing quantitative lipidomics, we analyze phospholipids present within human autophagic vesicles purified upon basal autophagy, starvation, and proteasome inhibition. Importantly, besides phosphoglycerides, we identify sphingomyelin within autophagic vesicles and show that the phospholipid composition is unaffected by the different conditions. Employing quantitative proteomics, we obtain cargo profiles of autophagic vesicles isolated upon the different treatment paradigms. Interestingly, starvation shows only subtle effects, while proteasome inhibition results in the enhanced presence of ubiquitin-proteasome pathway factors within autophagic vesicles. Thus, here we present a powerful method for the isolation of native autophagic vesicles, which enabled profound phospholipid and cargo analyses.
    Keywords:  autophagic vesicles; autophagy; cargo profiling; lipid profiling; vesicle isolation
    DOI:  https://doi.org/10.15252/embr.202153065
  7. FEBS Lett. 2022 Oct 10.
    Disulfide Bond Formation and Redox Regulation in the Golgi Apparatus.
    Nava Reznik, Deborah Fass.
      Formation of disulfide bonds in secreted and cell-surface proteins involves numerous enzymes and chaperones abundant in the endoplasmic reticulum (ER), the first and main site for disulfide bonding in the secretory pathway. Although the Golgi apparatus is the major station after the ER, little is known about thiol-based redox activity in this compartment. QSOX1 and its paralog QSOX2 are the only known Golgi-resident enzymes catalyzing disulfide bonding. Their conservation in animal cells and localization in an organelle downstream of the ER in the secretory pathway has long been puzzling. Recently, it has emerged that QSOX1 regulates particular glycosyltransferases, thereby influencing a central activity of the Golgi. Surprisingly, a few important disulfide-mediated multimerization events occurring in the Golgi were found to be independent of QSOX1. These multimerization events depend, however, on the low pH of the Golgi lumen and secretory granules. We compare and contrast disulfide-mediated multimerization in the ER vs. the Golgi to illustrate the variety of mechanisms controlling covalent supramolecular assembly of secreted proteins.
    Keywords:  Golgi; QSOX1; disulfide bonds; glycosyltransferases; mucins; redox regulation; secretory pathway; sialic acid; von Willebrand factor
    DOI:  https://doi.org/10.1002/1873-3468.14510
  8. Int J Mol Sci. 2022 Oct 05. pii: 11826. [Epub ahead of print]23(19):
    Endoplasmic Reticulum Homeostasis Regulates TLR4 Expression and Signaling in Mast Cells.
    Shatha Boukeileh, Odai Darawshi, Miriam Shmuel, Mohamed Mahameed, Thomas Wilhelm, Priya Dipta, Francesca Forno, Bellam Praveen, Michael Huber, Francesca Levi-Schaffer, Boaz Tirosh.
      The endoplasmic reticulum (ER) is a dynamic organelle that responds to demand in secretory proteins by undergoing expansion. The mechanisms that control the homeostasis of ER size and function involve the activation of the unfolded protein response (UPR). The UPR plays a role in various effector functions of immune cells. Mast cells (MCs) are highly granular tissue-resident cells and key drivers of allergic inflammation. Their diverse secretory functions in response to activation through the high-affinity receptor for IgE (FcεRI) suggest a role for the UPR in their function. Using human cord blood-derived MCs, we found that FcεRI triggering elevated the expression level and induced activation of the UPR transducers IRE1α and PERK, accompanied by expansion of the ER. In mouse bone marrow-derived MCs and peritoneal MCs, the ER underwent a more moderate expansion, and the UPR was not induced following MC activation. The deletion of IRE1α in mouse MCs did not affect proliferation, survival, degranulation, or cytokine stimulation following FcεRI triggering, but it did diminish the surface expression of TLR4 and the consequent response to LPS. A similar phenotype was observed in human MCs using an IRE1α inhibitor. Our data indicate that the ER of MCs, primarily of humans, undergoes a rapid remodeling in response to activation that promotes responses to TLR4. We suggest that IRE1α inhibition can be a strategy for inhibiting the hyperactivation of MCs by LPS over the course of allergic responses.
    Keywords:  ER stress; ER-phagy; TLR4; UPR; asthma; mast cells
    DOI:  https://doi.org/10.3390/ijms231911826
  9. Cell Signal. 2022 Oct 11. pii: S0898-6568(22)00252-2. [Epub ahead of print] 110490
    Novel insights into the non-canonical roles of PSMD14/POH1/Rpn11 in proteostasis and in the modulation of cancer progression.
    H A Bustamante, N Albornoz, E Morselli, A Soza, P V Burgos.
      PSMD14/POH1/Rpn11 plays a crucial role in cellular homeostasis. PSMD14 is a structural subunit of the lid subcomplex of the proteasome 19S regulatory particle with constitutive deubiquitinase activity. Canonically, PSMD14 removes the full ubiquitin chains with K48-linkages by hydrolyzing the isopeptide bond between the substrate and the C-terminus of the first ubiquitin, a crucial step for the entry of substrates into the catalytic barrel of the 20S proteasome and their subsequent degradation, all in context of the 26S proteasome. However, more recent discoveries indicate PSMD14 DUB activity is not only coupled to the translocation of substrates into the core of 20S proteasome. During the assembly of the lid, activity of PSMD14 has been detected in the context of the heterodimer with PSMD7. Additionally, assembly of the lid subcomplex occurs as an independent event of the base subcomplex and 20S proteasome. This feature opens the possibility that the regulatory particle, free lid subcomplex or the heterodimer PSMD14-PSMD7 might play other physiological roles including a positive function on protein stability through deubiquitination. Here we discuss scenarios that could enhance this PSMD14 non-canonical pathway, the potential impact in preventing degradation of substrates by autophagy highlighting the main findings that support this hypothesis. Finally, we discuss why this information should be investigated in biomedicine specifically with focus on cancer progression to design new therapeutic strategies against the lid subcomplex and the heterodimer PSMD14-PSMD7, highlighting PSMD14 as a druggable target for cancer therapy.
    Keywords:  Autophagy; Cancer progression; Deubiquitinase; Proteasome assembly; Proteostasis; Substrate stabilization
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110490
  10. Elife. 2022 Oct 11. pii: e79570. [Epub ahead of print]11
    Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation.
    Mahlon A Collins, Gemechu Mekonnen, Frank Wolfgang Albert.
      Precise control of protein degradation is critical for life, yet how natural genetic variation affects this essential process is largely unknown. Here, we developed a statistically powerful mapping approach to characterize how genetic variation affects protein degradation by the ubiquitin-proteasome system (UPS). Using the yeast Saccharomyces cerevisiae, we systematically mapped genetic influences on the N-end rule, a UPS pathway in which protein N-terminal amino acids function as degradation-promoting signals. Across all 20 possible N-terminal amino acids, we identified 149 genomic loci that influence UPS activity, many of which had pathway- or substrate-specific effects. Fine-mapping of four loci identified multiple causal variants in each of four ubiquitin system genes whose products process (NTA1), recognize (UBR1 and DOA10), and ubiquitinate (UBC6) cellular proteins. A cis-acting promoter variant that modulates UPS activity by altering UBR1 expression alters the abundance of 36 proteins without affecting levels of the corresponding mRNAs. Our results reveal a complex genetic basis of variation in UPS activity.
    Keywords:  S. cerevisiae; genetics; genomics
    DOI:  https://doi.org/10.7554/eLife.79570
  11. Proc Natl Acad Sci U S A. 2022 Oct 18. 119(42): e2209427119
    Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition.
    Elma S Frias, Mahmood S Hoseini, Karen Krukowski, Maria Serena Paladini, Katherine Grue, Gonzalo Ureta, Kira D A Rienecker, Peter Walter, Michael P Stryker, Susanna Rosi.
      Traumatic brain injury (TBI) is a leading cause of long-term neurological disability in the world and the strongest environmental risk factor for the development of dementia. Even mild TBI (resulting from concussive injuries) is associated with a greater than twofold increase in the risk of dementia onset. Little is known about the cellular mechanisms responsible for the progression of long-lasting cognitive deficits. The integrated stress response (ISR), a phylogenetically conserved pathway involved in the cellular response to stress, is activated after TBI, and inhibition of the ISR-even weeks after injury-can reverse behavioral and cognitive deficits. However, the cellular mechanisms by which ISR inhibition restores cognition are unknown. Here, we used longitudinal two-photon imaging in vivo after concussive injury in mice to study dendritic spine dynamics in the parietal cortex, a brain region involved in working memory. Concussive injury profoundly altered spine dynamics measured up to a month after injury. Strikingly, brief pharmacological treatment with the drug-like small-molecule ISR inhibitor ISRIB entirely reversed structural changes measured in the parietal cortex and the associated working memory deficits. Thus, both neural and cognitive consequences of concussive injury are mediated in part by activation of the ISR and can be corrected by its inhibition. These findings suggest that targeting ISR activation could serve as a promising approach to the clinical treatment of chronic cognitive deficits after TBI.
    Keywords:  closed-head injury; dendritic spine; integrated stress response; in vivo two-photon imaging; mouse parietal cortex
    DOI:  https://doi.org/10.1073/pnas.2209427119
  12. J Cell Biol. 2023 Jan 02. pii: e202203045. [Epub ahead of print]222(1):
    Convergence of secretory, endosomal, and autophagic routes in trans-Golgi-associated lysosomes.
    Lingjian Zhou, Xutong Xue, Ke Yang, Zhi Feng, Min Liu, José C Pastor-Pareja.
      At the trans-Golgi, complex traffic connections exist to the endolysosomal system additional to the main Golgi-to-plasma membrane secretory route. Here, we investigated three hits in a Drosophila screen displaying secretory cargo accumulation in autophagic vesicles: ESCRT-III component Vps20, SNARE-binding Rop, and lysosomal pump subunit VhaPPA1-1. We found that Vps20, Rop, and lysosomal markers localize near the trans-Golgi. Furthermore, we document that the vicinity of the trans-Golgi is the main cellular location for lysosomes and that early, late, and recycling endosomes associate as well with a trans-Golgi-associated degradative compartment where basal microautophagy of secretory cargo and other materials occurs. Disruption of this compartment causes cargo accumulation in our hits, including Munc18 homolog Rop, required with Syx1 and Syx4 for Rab11-mediated endosomal recycling. Finally, besides basal microautophagy, we show that the trans-Golgi-associated degradative compartment contributes to the growth of autophagic vesicles in developmental and starvation-induced macroautophagy. Our results argue that the fly trans-Golgi is the gravitational center of the whole endomembrane system.
    DOI:  https://doi.org/10.1083/jcb.202203045
  13. Exp Cell Res. 2022 Oct 06. pii: S0014-4827(22)00369-X. [Epub ahead of print]421(1): 113376
    IRE1α-XBP1 regulates PDK1-dependent induction of epithelial-mesenchymal transition in non-small cell lung cancer cells.
    Xike Mao, Chenxi Yu, Feng Yin, Wenjiao Xu, Yonghan Pan, Bowen Yang, Tao Huang, Siling Chen, Wenge Luo, Tianyu Su, Zhihao Wu.
      Mounting evidence indicates that activation of unfolded protein response (UPR) and metabolic reprogramming contribute to cancer cell migration and invasion, but the molecular mechanism of pro-EMT program through a coordinated action of UPR with metabolism has not been defined. In this study, we utilized ER stress-inducing reagent, thapsigargin (TG), to induced pharmacologic ER stress in lung cancer cells. Here. We report that the branch of UPR, IRE1α-XBP1 pathway plays a pivotal role in reprogramming lung cancer cell metabolism. At the molecular level, the expression of pyruvate dehydrogenase kinase-1 (PDK-1) is directly induced by XBP1 as a consequence of UPR activation, thus facilitating aerobic glycolysis and lactate production. We also demonstrated that PDK1 serves as a downstream element of UPR activation in induction of Snail and EMT program. In addition, PDK1-induced Snail was dependent on the lactate production derived from metabolic reprogramming. Our findings reveal a critical role of lactate in pro-invasion events and establishes a direct connection between ER-stress and metabolic reprogramming in facilitating cancer cell progression.
    Keywords:  IRE1α-XBP1 pathway; Metabolic reprogramming; Pyruvate dehydrogenase kinase-1 (PDK-1); Snail; Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113376
  14. J Cell Sci. 2022 Oct 13. pii: jcs.259734. [Epub ahead of print]
    Genetic deletion of hspa8 leads to selective tissue malformations in zebrafish embryonic development.
    Caixia Wang, Xin Zhang, Xinyu Wang, Yanpeng Zhai, Mengjiao Li, Jun Pan, Yan Bai, Xiaozhi Rong, Jianfeng Zhou.
      The heat shock cognate 71 kDa protein HSPA8/HSC70, a constitutively expressed cognate member of the heat shock protein 70 family, plays an essential role in protein quality control and cell homeostasis maintenance. HSPA8 has been implicated in many diseases, including cancers and neurodegenerative diseases. Due to massive cell death after knockdown of HSPA8 and nonviable Hspa8 knockout mice, the physiological role of HSPA8 in vertebrates and its underlying mechanism have not yet been elucidated. To address this issue, we used CRISPR/Cas9 technology and genetically deleted hspa8 in zebrafish embryos. Genetic deletion of hspa8 resulted in malformations of the pharyngeal arches, pectoral fins, head, and eyes at the later stages. We next focused on pharyngeal arch deficiency and found that pharyngeal arches in hspa8 mutant embryos exhibited induction of endoplasmic reticulum stress and activation of the unfolded protein response via the Perk/p-eIF2α/Atf4 signaling cascade. Inhibition of Perk/p-eIF2α/Atf4 signaling rescued developmental deficiency of pharyngeal arches due to depletion of Hspa8. Taken together, our results provide novel insights into the tissue-specific roles of Hspa8 in the regulation of vertebrate embryonic development.
    Keywords:  ATF4; Hspa8/Hsc70; Pharyngeal arch cartilages; Unfolded protein response; Zebrafish; eIF2α
    DOI:  https://doi.org/10.1242/jcs.259734
  15. Cell Rep. 2022 Oct 11. pii: S2211-1247(22)01317-1. [Epub ahead of print]41(2): 111467
    An unusual mode of baseline translation adjusts cellular protein synthesis capacity to metabolic needs.
    Cornelius Schneider, Florian Erhard, Beyenech Binotti, Alexander Buchberger, Jörg Vogel, Utz Fischer.
      In all domains of life, mechanisms exist that adjust translational capacity to nutrient restriction and other growth constraints. The mammalian target of rapamycin (mTOR) regulates the synthesis of ribosomal proteins and translation factors in mammalian cells via phosphorylation of the La-related protein 1 (LARP1). In the present model of starvation-induced translational silencing, LARP1 targets mRNAs carrying a 5' terminal oligopyrimidine (5'TOP) motif to shift these into subpolysomal ribonucleoprotein particles. However, how these mRNAs would be protected from degradation and rapidly made available to restore translation capacity when needed remained enigmatic. Here, to address this, we employ gradient profiling by sequencing (Grad-seq) and monosome footprinting. Challenging the above model, we find that 5'TOP mRNAs, instead of being translationally silenced during starvation, undergo low baseline translation with reduced initiation rates. This mode of regulation ensures a stable 5'TOP mRNA population under starvation and allows fast reversibility of the translational repression.
    Keywords:  5'TOP; CP: Molecular biology; LARP1; TOP mRNAs; TOP response; baseline translation; mRNA; mTORC1; starvation; translation initiation; translation regulation
    DOI:  https://doi.org/10.1016/j.celrep.2022.111467
  16. EMBO J. 2022 Oct 11. e111289
    Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection.
    Subhash Mehto, Kautilya Kumar Jena, Rina Yadav, Swatismita Priyadarsini, Pallavi Samal, Sivaram Krishna, Kollori Dhar, Ashish Jain, Nishant Ranjan Chauhan, Krushna C Murmu, Ramyasingh Bal, Rinku Sahu, Pundrik Jaiswal, Bhabani Sankar Sahoo, Srinivas Patnaik, Thomas A Kufer, Tor Erik Rusten, Swati Chauhan, Punit Prasad, Santosh Chauhan.
      The NOD1/2-RIPK2 is a key cytosolic signaling complex that activates NF-κB pro-inflammatory response against invading pathogens. However, uncontrolled NF-κB signaling can cause tissue damage leading to chronic diseases. The mechanisms by which the NODs-RIPK2-NF-κB innate immune axis is activated and resolved remain poorly understood. Here, we demonstrate that bacterial infection induces the formation of endogenous RIPK2 oligomers (RIPosomes) that are self-assembling entities that coat the bacteria to induce NF-κB response. Next, we show that autophagy proteins IRGM and p62/SQSTM1 physically interact with NOD1/2, RIPK2 and RIPosomes to promote their selective autophagy and limit NF-κB activation. IRGM suppresses RIPK2-dependent pro-inflammatory programs induced by Shigella and Salmonella. Consistently, the therapeutic inhibition of RIPK2 ameliorates Shigella infection- and DSS-induced gut inflammation in Irgm1 KO mice. This study identifies a unique mechanism where the innate immune proteins and autophagy machinery are recruited together to the bacteria for defense as well as for maintaining immune homeostasis.
    Keywords:  Irgm1; NOD1/2-RIPK2-NF-κB; RIPosomes; autophagy; inflammation
    DOI:  https://doi.org/10.15252/embj.2022111289
  17. EMBO J. 2022 Oct 11. e112059
    The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α.
    Daisheng Song, Kai Peng, Bradleigh E Palmer, Frank S Lee.
      Prolyl hydroxylase domain protein 2 (PHD2)-catalyzed modification of hypoxia-inducible factor (HIF)-α is a key event in oxygen sensing. We previously showed that the zinc finger of PHD2 binds to a Pro-Xaa-Leu-Glu (PXLE) motif. Here, we show that the zinc finger binds to this motif in the ribosomal chaperone nascent polypeptide complex-α (NACA). This recruits PHD2 to the translation machinery to cotranslationally modify HIF-α. Importantly, this cotranslational modification is enhanced by a translational pause sequence in HIF-α. Mice with a knock-in Naca gene mutation that abolishes the PXLE motif display erythrocytosis, a reflection of HIF pathway dysregulation. In addition, human erythrocytosis-associated mutations in the zinc finger of PHD2 ablate interaction with NACA. Tibetans, who have adapted to the hypoxia of high altitude, harbor a PHD2 variant that we previously showed displays a defect in zinc finger binding to p23, a PXLE-containing HSP90 cochaperone. We show here that Tibetan PHD2 maintains interaction with NACA, thereby showing differential interactions with PXLE-containing proteins and providing an explanation for why Tibetans are not predisposed to erythrocytosis.
    Keywords:  NACA; Tibetan adaptation; hypoxia-inducible factor; prolyl hydroxylase domain protein 2
    DOI:  https://doi.org/10.15252/embj.2022112059
  18. EMBO J. 2022 Oct 10. e111115
    BNIP3L/NIX regulates both mitophagy and pexophagy.
    Léa P Wilhelm, Juan Zapata-Muñoz, Beatriz Villarejo-Zori, Stephanie Pellegrin, Catarina Martins Freire, Ashley M Toye, Patricia Boya, Ian G Ganley.
      Mitochondria and peroxisomes are closely related metabolic organelles, both in terms of origin and in terms of function. Mitochondria and peroxisomes can also be turned over by autophagy, in processes termed mitophagy and pexophagy, respectively. However, despite their close relationship, it is not known if both organelles are turned over under similar conditions, and if so, how this might be coordinated molecularly. Here, we find that multiple selective autophagy pathways are activated upon iron chelation and show that mitophagy and pexophagy occur in a BNIP3L/NIX-dependent manner. We reveal that the outer mitochondrial membrane-anchored NIX protein, previously described as a mitophagy receptor, also independently localises to peroxisomes and drives pexophagy. We show this process happens in vivo, with mouse tissue that lacks NIX having a higher peroxisomal content. We further show that pexophagy is stimulated under the same physiological conditions that activate mitophagy, including cardiomyocyte and erythrocyte differentiation. Taken together, our work uncovers a dual role for NIX, not only in mitophagy but also in pexophagy, thus illustrating the interconnection between selective autophagy pathways.
    Keywords:  autophagy; mitochondria; mitophagy; peroxisomes; pexophagy
    DOI:  https://doi.org/10.15252/embj.2022111115
  19. Nat Commun. 2022 Oct 10. 13(1): 5986
    Membrane-assisted assembly and selective secretory autophagy of enteroviruses.
    Selma Dahmane, Adeline Kerviel, Dustin R Morado, Kasturika Shankar, Björn Ahlman, Michael Lazarou, Nihal Altan-Bonnet, Lars-Anders Carlson.
      Enteroviruses are non-enveloped positive-sense RNA viruses that cause diverse diseases in humans. Their rapid multiplication depends on remodeling of cytoplasmic membranes for viral genome replication. It is unknown how virions assemble around these newly synthesized genomes and how they are then loaded into autophagic membranes for release through secretory autophagy. Here, we use cryo-electron tomography of infected cells to show that poliovirus assembles directly on replication membranes. Pharmacological untethering of capsids from membranes abrogates RNA encapsidation. Our data directly visualize a membrane-bound half-capsid as a prominent virion assembly intermediate. Assembly progression past this intermediate depends on the class III phosphatidylinositol 3-kinase VPS34, a key host-cell autophagy factor. On the other hand, the canonical autophagy initiator ULK1 is shown to restrict virion production since its inhibition leads to increased accumulation of virions in vast intracellular arrays, followed by an increased vesicular release at later time points. Finally, we identify multiple layers of selectivity in virus-induced autophagy, with a strong selection for RNA-loaded virions over empty capsids and the segregation of virions from other types of autophagosome contents. These findings provide an integrated structural framework for multiple stages of the poliovirus life cycle.
    DOI:  https://doi.org/10.1038/s41467-022-33483-7
  20. Nat Commun. 2022 Oct 10. 13(1): 5973
    The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS.
    Tian-Chen Xiong, Ming-Cong Wei, Fang-Xu Li, Miao Shi, Hu Gan, Zhen Tang, Hong-Peng Dong, Tianzi Liuyu, Pu Gao, Bo Zhong, Zhi-Dong Zhang, Dandan Lin.
      The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays a critical role in antiviral immunity and autoimmunity. The activity and stability of cGAS are fine-tuned by post-translational modifications. Here, we show that ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) catalyzes the mono-ISGylation and induces the oligomerization of cGAS, thereby promoting antiviral immunity and autoimmunity. Knockdown or knockout of ARIH1 significantly inhibits herpes simplex virus 1 (HSV-1)- or cytoplasmic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Consistently, tamoxifen-treated ER-Cre;Arih1fl/fl mice and Lyz2-Cre; Arih1fl/fl mice are hypersensitive to HSV-1 infection compared with the controls. In addition, deletion of ARIH1 in myeloid cells alleviates the autoimmune phenotypes and completely rescues the autoimmune lethality caused by TREX1 deficiency. Mechanistically, HSV-1- or cytosolic DNA-induced oligomerization and activation of cGAS are potentiated by ISGylation at its K187 residue, which is catalyzed by ARIH1. Our findings thus reveal an important role of ARIH1 in innate antiviral and autoimmune responses and provide insight into the post-translational regulation of cGAS.
    DOI:  https://doi.org/10.1038/s41467-022-33671-5
  21. Nat Commun. 2022 Oct 10. 13(1): 5969
    A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.
    Christiane Kofink, Nicole Trainor, Barbara Mair, Simon Wöhrle, Melanie Wurm, Nikolai Mischerikow, Michael J Roy, Gerd Bader, Peter Greb, Géraldine Garavel, Emelyne Diers, Ross McLennan, Claire Whitworth, Vesna Vetma, Klaus Rumpel, Maximilian Scharnweber, Julian E Fuchs, Thomas Gerstberger, Yunhai Cui, Gabriela Gremel, Paolo Chetta, Stefan Hopf, Nicole Budano, Joerg Rinnenthal, Gerhard Gmaschitz, Moriz Mayer, Manfred Koegl, Alessio Ciulli, Harald Weinstabl, William Farnaby.
      Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.
    DOI:  https://doi.org/10.1038/s41467-022-33430-6
  22. Biochem Biophys Res Commun. 2022 Sep 29. pii: S0006-291X(22)01360-2. [Epub ahead of print]632 158-164
    KIRA8 attenuates non-alcoholic steatohepatitis through inhibition of the IRE1α/XBP1 signalling pathway.
    Shiting Zhao, Xiaomin Liu, Lei Li, Xinyu Kong, Wei Sun, Kerry Loomes, Tao Nie, Xiaoyan Hui, Donghai Wu.
      Endoplasmic reticulum (ER) stress is enhanced in non-alcoholic steatohepatitis (NASH). Among three signalling pathways, the IRE1α/XBP1 signalling pathway is strongly implicated in the pathogenesis of NASH but its significance is still largely uncharacterised. In this report, we constructed a hepatocyte-specific XBP1-Luciferase knock-in mouse model that allows in vivo monitoring of the IRE1α/XBP1 activity in hepatocytes. Using this mouse model, we found that IRE1α/XBP1 was activated within hepatocytes during the pathogenesis of NASH. Significantly, a specific IRE1α kinase-inhibiting RNase attenuator, KIRA8, attenuated NASH in mice. In conclusion, our hepatocyte-specific XBP1 splicing reporter mouse represents a valid model for research and drug development of NASH, which showed that the IRE1α-induced XBP splicing is potentiated in hepatocytes during pathogenesis of NASH. Furthermore, we carried out the proof-of-concept study to demonstrate that the allosteric IRE1α RNase inhibitor serves as a promising therapeutic agent for the treatment of NASH.
    Keywords:  IRE1α; KIRA8; NASH; Reporter mouse model; XBP1 splicing
    DOI:  https://doi.org/10.1016/j.bbrc.2022.09.098
  23. Nat Commun. 2022 Oct 12. 13(1): 6028
    Predicting the structure of large protein complexes using AlphaFold and Monte Carlo tree search.
    Patrick Bryant, Gabriele Pozzati, Wensi Zhu, Aditi Shenoy, Petras Kundrotas, Arne Elofsson.
      AlphaFold can predict the structure of single- and multiple-chain proteins with very high accuracy. However, the accuracy decreases with the number of chains, and the available GPU memory limits the size of protein complexes which can be predicted. Here we show that one can predict the structure of large complexes starting from predictions of subcomponents. We assemble 91 out of 175 complexes with 10-30 chains from predicted subcomponents using Monte Carlo tree search, with a median TM-score of 0.51. There are 30 highly accurate complexes (TM-score ≥0.8, 33% of complete assemblies). We create a scoring function, mpDockQ, that can distinguish if assemblies are complete and predict their accuracy. We find that complexes containing symmetry are accurately assembled, while asymmetrical complexes remain challenging. The method is freely available and accesible as a Colab notebook https://colab.research.google.com/github/patrickbryant1/MoLPC/blob/master/MoLPC.ipynb .
    DOI:  https://doi.org/10.1038/s41467-022-33729-4
  24. Methods Enzymol. 2022 ;pii: S0076-6879(22)00242-7. [Epub ahead of print]675 63-82
    Synthesis of O-GlcNAcylated small heat shock proteins.
    Stuart P Moon, Matthew R Pratt.
      A protein's structure and function often depend not only on its primary sequence, but also the presence or absence of any number of non-coded posttranslational modifications. Complicating their study is the fact that the physiological consequences of these modifications are context-, protein-, and site-dependent, and there exist no purely biological techniques to unambiguously study their effects. To this end, protein semisynthesis has become an invaluable chemical biology tool to specifically install non-coded or non-native moieties onto proteins in vitro using synthetic and/or recombinant polypeptides. Here, we describe two facets of protein semisynthesis (solid-phase peptide synthesis and expressed protein ligation) and their use in generating site-specifically glycosylated small heat shock proteins for functional studies. The procedures herein require limited specialized equipment, employ mild reaction conditions, and can be extended to myriad other proteins, modifications, and contexts.
    Keywords:  Chaperone; Chemical ligation; Heat shock protein; O-GlcNAc; Posttranslational modification
    DOI:  https://doi.org/10.1016/bs.mie.2022.07.004
  25. Chem Soc Rev. 2022 Oct 11.
    Emerging degrader technologies engaging lysosomal pathways.
    Yu Ding, Dong Xing, Yiyan Fei, Boxun Lu.
      Targeted protein degradation (TPD) provides unprecedented opportunities for drug discovery. While the proteolysis-targeting chimera (PROTAC) technology has already entered clinical trials and changed the landscape of small-molecule drugs, new degrader technologies harnessing alternative degradation machineries, especially lysosomal pathways, have emerged and broadened the spectrum of degradable targets. We have recently proposed the concept of autophagy-tethering compounds (ATTECs) that hijack the autophagy protein microtubule-associated protein 1A/1B light chain 3 (LC3) for targeted degradation. Other groups also reported degrader technologies engaging lysosomal pathways through different mechanisms including AUTACs, AUTOTACs, LYTACs and MoDE-As. In this review, we analyse and discuss ATTECs along with other lysosomal-relevant degrader technologies. Finally, we will briefly summarize the current status of these degrader technologies and envision possible future studies.
    DOI:  https://doi.org/10.1039/d2cs00624c
  26. EMBO Rep. 2022 Oct 10. e55470
    The Autophagy Receptor TAX1BP1 (T6BP) improves antigen presentation by MHC-II molecules.
    Gabriela Sarango, Clémence Richetta, Mathias Pereira, Anita Kumari, Michael Ghosh, Lisa Bertrand, Cédric Pionneau, Morgane Le Gall, Sylvie Grégoire, Raphaël Jeger-Madiot, Elina Rosoy, Frédéric Subra, Olivier Delelis, Mathias Faure, Audrey Esclatine, Stéphanie Graff-Dubois, Stefan Stevanović, Bénédicte Manoury, Bertha Cecilia Ramirez, Arnaud Moris.
      CD4+ T lymphocytes play a major role in the establishment and maintenance of immunity. They are activated by antigenic peptides derived from extracellular or newly synthesized (endogenous) proteins presented by the MHC-II molecules. The pathways leading to endogenous MHC-II presentation remain poorly characterized. We demonstrate here that the autophagy receptor, T6BP, influences both autophagy-dependent and -independent endogenous presentation of HIV- and HCMV-derived peptides. By studying the immunopeptidome of MHC-II molecules, we show that T6BP affects both the quantity and quality of peptides presented. T6BP silencing induces the mislocalization of the MHC-II-loading compartments and rapid degradation of the invariant chain (CD74) without altering the expression and internalization kinetics of MHC-II molecules. Defining the interactome of T6BP, we identify calnexin as a T6BP partner. We show that the calnexin cytosolic tail is required for this interaction. Remarkably, calnexin silencing replicates the functional consequences of T6BP silencing: decreased CD4+ T cell activation and exacerbated CD74 degradation. Altogether, we unravel T6BP as a key player of the MHC-II-restricted endogenous presentation pathway, and we propose one potential mechanism of action.
    Keywords:  CD4+ T cell activation; calnexin; immunopeptidome; interactome; virus
    DOI:  https://doi.org/10.15252/embr.202255470
  27. J Med Chem. 2022 Oct 11.
    Discovery of Potent OTUB1/USP8 Dual Inhibitors Targeting Proteostasis in Non-Small-Cell Lung Cancer.
    Lingli Tan, Hengyue Shan, Chao Han, Zhenfeng Zhang, Jiali Shen, Xiao Zhang, Huaijiang Xiang, Kuankuan Lu, Chunting Qi, Ying Li, Guanglei Zhuang, Gang Chen, Li Tan.
      Deubiquitinating enzymes (DUBs) are key regulatory components of the ubiquitination system. Many DUBs have been revealed to play key roles in normal physiology and diseases. However, only very limited DUB members have well-characterized inhibitors. OTUB1 and USP8 are two DUBs reported to promote both immune evasion and tumorigenesis in tumor models, yet their targeted inhibitors are in the early stages of development. Here, we describe the lead identification and optimization of an OTUB1/USP8 dual inhibitor, 61, which exhibits highly potent and selective inhibition of both targets with subnanomolar IC50s in vitro. By inhibiting both DUBs, 61 phenocopies the double knockdown of OTUB1/USP8 and exerts pronounced antiproliferative effects in H1975 and other non-small-cell lung cancer (NSCLC) cell lines. Moreover, 61 efficaciously mitigates tumor growth in vivo. Collectively, our results provide a useful tool for pharmacological perturbation of OTUB1/USP8 and introduce a promising therapeutic strategy of dual DUB inhibition for treating NSCLC.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c00408
  28. Proc Natl Acad Sci U S A. 2022 Oct 18. 119(42): e2203750119
    Proximity proteomics of synaptopodin provides insight into the molecular composition of the spine apparatus of dendritic spines.
    Hanieh Falahati, Yumei Wu, Vanessa Feuerer, Hans-Georg Simon, Pietro De Camilli.
      The spine apparatus is a specialized compartment of the neuronal smooth endoplasmic reticulum (ER) located in a subset of dendritic spines. It consists of stacks of ER cisterns that are interconnected by an unknown dense matrix and are continuous with each other and with the ER of the dendritic shaft. While this organelle was first observed over 60 y ago, its molecular organization remains a mystery. Here, we performed in vivo proximity proteomics to gain some insight into its molecular components. To do so, we used the only known spine apparatus-specific protein, synaptopodin, to target a biotinylating enzyme to this organelle. We validated the specific localization in dendritic spines of a small subset of proteins identified by this approach, and we further showed their colocalization with synaptopodin when expressed in nonneuronal cells. One such protein is Pdlim7, an actin binding protein not previously identified in spines. Pdlim7, which we found to interact with synaptopodin through multiple domains, also colocalizes with synaptopodin on the cisternal organelle, a peculiar stack of ER cisterns resembling the spine apparatus and found at axon initial segments of a subset of neurons. Moreover, Pdlim7 has an expression pattern similar to that of synaptopodin in the brain, highlighting a functional partnership between the two proteins. The components of the spine apparatus identified in this work will help elucidate mechanisms in the biogenesis and maintenance of this enigmatic structure with implications for the function of dendritic spines in physiology and disease.
    Keywords:  Pdlim7; dendritic spine; iBioID; in vivo proximity proteomics; spine apparatus
    DOI:  https://doi.org/10.1073/pnas.2203750119
  29. Trends Mol Med. 2022 Oct 11. pii: S1471-4914(22)00242-8. [Epub ahead of print]
    Dysfunctional tRNA reprogramming and codon-biased translation in cancer.
    Peter C Dedon, Thomas J Begley.
      Many cancers hijack translation to increase the synthesis of tumor-driving proteins, the messenger mRNAs of which have specific codon usage patterns. Termed 'codon-biased translation' and originally identified in stress response regulation, this mechanism is supported by diverse studies demonstrating how the 50 RNA modifications of the epitranscriptome, specific tRNAs, and codon-biased mRNAs are used by oncogenic programs to promote proliferation and chemoresistance. The epitranscriptome writers METTL1-WDR4, Elongator complex protein (ELP)1-6, CTU1-2, and ALKBH8-TRM112 illustrate the principal mechanism of codon-biased translation, with gene amplifications, increased RNA modifications, and enhanced tRNA stability promoting cancer proliferation. Furthermore, systems-level analyses of 34 tRNA writers and 493 tRNA genes highlight the theme of tRNA epitranscriptome dysregulation in many cancers and identify candidate tRNA writers, tRNA modifications, and tRNA molecules as drivers of pathological codon-biased translation.
    Keywords:  cancer; codon; epitranscriptome; gene expression; systems biology; tRNA modifications; translational regulation
    DOI:  https://doi.org/10.1016/j.molmed.2022.09.007
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