The EMBO JournalPub Date : 2022-09-15Epub Date: 2022-08-03DOI: 10.15252/embj.2021109353
Dawei Chen, Ivan Nemazanyy, Olivier Peulen, Kateryna Shostak, Xinyi Xu, Seng Chuan Tang, Caroline Wathieu, Silvia Turchetto, Sylvia Tielens, Laurent Nguyen, Pierre Close, Christophe Desmet, Sebastian Klein, Alexandra Florin, Reinhard Büttner, Georgios Petrellis, Benjamin Dewals, Alain Chariot
{"title":"Elp3-mediated codon-dependent translation promotes mTORC2 activation and regulates macrophage polarization.","authors":"Dawei Chen, Ivan Nemazanyy, Olivier Peulen, Kateryna Shostak, Xinyi Xu, Seng Chuan Tang, Caroline Wathieu, Silvia Turchetto, Sylvia Tielens, Laurent Nguyen, Pierre Close, Christophe Desmet, Sebastian Klein, Alexandra Florin, Reinhard Büttner, Georgios Petrellis, Benjamin Dewals, Alain Chariot","doi":"10.15252/embj.2021109353","DOIUrl":"https://doi.org/10.15252/embj.2021109353","url":null,"abstract":"<p><p>Macrophage polarization is a process whereby macrophages acquire distinct effector states (M1 or M2) to carry out multiple and sometimes opposite functions. We show here that translational reprogramming occurs during macrophage polarization and that this relies on the Elongator complex subunit Elp3, an enzyme that modifies the wobble uridine base U34 in cytosolic tRNAs. Elp3 expression is downregulated by classical M1-activating signals in myeloid cells, where it limits the production of pro-inflammatory cytokines via FoxO1 phosphorylation, and attenuates experimental colitis in mice. In contrast, alternative M2-activating signals upregulate Elp3 expression through a PI3K- and STAT6-dependent signaling pathway. The metabolic reprogramming linked to M2 macrophage polarization relies on Elp3 and the translation of multiple candidates, including the mitochondrial ribosome large subunit proteins Mrpl3, Mrpl13, and Mrpl47. By promoting translation of its activator Ric8b in a codon-dependent manner, Elp3 also regulates mTORC2 activation. Elp3 expression in myeloid cells further promotes Wnt-driven tumor initiation in the intestine by maintaining a pool of tumor-associated macrophages exhibiting M2 features. Collectively, our data establish a functional link between tRNA modifications, mTORC2 activation, and macrophage polarization.</p>","PeriodicalId":305851,"journal":{"name":"The EMBO Journal","volume":" ","pages":"e109353"},"PeriodicalIF":11.4,"publicationDate":"2022-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9475509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40677295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The EMBO JournalPub Date : 2022-09-01Epub Date: 2022-07-20DOI: 10.15252/embj.2022110784
Silja Lucia Salscheider, Sarah Gerlich, Alfredo Cabrera-Orefice, Esra Peker, Robin Alexander Rothemann, Lena Maria Murschall, Yannik Finger, Karolina Szczepanowska, Zeinab Alsadat Ahmadi, Sergio Guerrero-Castillo, Alican Erdogan, Mark Becker, Muna Ali, Markus Habich, Carmelina Petrungaro, Nele Burdina, Guenter Schwarz, Merlin Klußmann, Ines Neundorf, David A Stroud, Michael T Ryan, Aleksandra Trifunovic, Ulrich Brandt, Jan Riemer
{"title":"AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5.","authors":"Silja Lucia Salscheider, Sarah Gerlich, Alfredo Cabrera-Orefice, Esra Peker, Robin Alexander Rothemann, Lena Maria Murschall, Yannik Finger, Karolina Szczepanowska, Zeinab Alsadat Ahmadi, Sergio Guerrero-Castillo, Alican Erdogan, Mark Becker, Muna Ali, Markus Habich, Carmelina Petrungaro, Nele Burdina, Guenter Schwarz, Merlin Klußmann, Ines Neundorf, David A Stroud, Michael T Ryan, Aleksandra Trifunovic, Ulrich Brandt, Jan Riemer","doi":"10.15252/embj.2022110784","DOIUrl":"10.15252/embj.2022110784","url":null,"abstract":"<p><p>The mitochondrial intermembrane space protein AIFM1 has been reported to mediate the import of MIA40/CHCHD4, which forms the import receptor in the mitochondrial disulfide relay. Here, we demonstrate that AIFM1 and MIA40/CHCHD4 cooperate beyond this MIA40/CHCHD4 import. We show that AIFM1 and MIA40/CHCHD4 form a stable long-lived complex in vitro, in different cell lines, and in tissues. In HEK293 cells lacking AIFM1, levels of MIA40 are unchanged, but the protein is present in the monomeric form. Monomeric MIA40 neither efficiently interacts with nor mediates the import of specific substrates. The import defect is especially severe for NDUFS5, a subunit of complex I of the respiratory chain. As a consequence, NDUFS5 accumulates in the cytosol and undergoes rapid proteasomal degradation. Lack of mitochondrial NDUFS5 in turn results in stalling of complex I assembly. Collectively, we demonstrate that AIFM1 serves two overlapping functions: importing MIA40/CHCHD4 and constituting an integral part of the disulfide relay that ensures efficient interaction of MIA40/CHCHD4 with specific substrates.</p>","PeriodicalId":305851,"journal":{"name":"The EMBO Journal","volume":" ","pages":"e110784"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e8/9e/EMBJ-41-e110784.PMC9434101.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40524488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The EMBO JournalPub Date : 2022-09-01Epub Date: 2022-07-28DOI: 10.15252/embj.2022111650
Cathrine Nordgaard, Anna Constance Vind, Amy Stonadge, Rasmus Kjøbsted, Goda Snieckute, Pedro Antas, Melanie Blasius, Marie Sofie Reinert, Ana Martinez Del Val, Dorte Breinholdt Bekker-Jensen, Peter Haahr, Yekaterina A Miroshnikova, Abdelghani Mazouzi, Sarah Falk, Emeline Perrier-Groult, Christopher Tiedje, Xiang Li, Jens Rithamer Jakobsen, Nicolas Oldenburg Jørgensen, Jørgen Fp Wojtaszewski, Frederic Mallein-Gerin, Jesper Løvind Andersen, Cristian Pablo Pennisi, Christoffer Clemmensen, Moustapha Kassem, Abbas Jafari, Thijn Brummelkamp, Vivian Sw Li, Sara A Wickström, Jesper Velgaard Olsen, Gonzalo Blanco, Simon Bekker-Jensen
{"title":"ZAKβ is activated by cellular compression and mediates contraction-induced MAP kinase signaling in skeletal muscle.","authors":"Cathrine Nordgaard, Anna Constance Vind, Amy Stonadge, Rasmus Kjøbsted, Goda Snieckute, Pedro Antas, Melanie Blasius, Marie Sofie Reinert, Ana Martinez Del Val, Dorte Breinholdt Bekker-Jensen, Peter Haahr, Yekaterina A Miroshnikova, Abdelghani Mazouzi, Sarah Falk, Emeline Perrier-Groult, Christopher Tiedje, Xiang Li, Jens Rithamer Jakobsen, Nicolas Oldenburg Jørgensen, Jørgen Fp Wojtaszewski, Frederic Mallein-Gerin, Jesper Løvind Andersen, Cristian Pablo Pennisi, Christoffer Clemmensen, Moustapha Kassem, Abbas Jafari, Thijn Brummelkamp, Vivian Sw Li, Sara A Wickström, Jesper Velgaard Olsen, Gonzalo Blanco, Simon Bekker-Jensen","doi":"10.15252/embj.2022111650","DOIUrl":"10.15252/embj.2022111650","url":null,"abstract":"<p><p>Mechanical inputs give rise to p38 and JNK activation, which mediate adaptive physiological responses in various tissues. In skeletal muscle, contraction-induced p38 and JNK signaling ensure adaptation to exercise, muscle repair, and hypertrophy. However, the mechanisms by which muscle fibers sense mechanical load to activate this signaling have remained elusive. Here, we show that the upstream MAP3K ZAKβ is activated by cellular compression induced by osmotic shock and cyclic compression in vitro, and muscle contraction in vivo. This function relies on ZAKβ's ability to recognize stress fibers in cells and Z-discs in muscle fibers when mechanically perturbed. Consequently, ZAK-deficient mice present with skeletal muscle defects characterized by fibers with centralized nuclei and progressive adaptation towards a slower myosin profile. Our results highlight how cells in general respond to mechanical compressive load and how mechanical forces generated during muscle contraction are translated into MAP kinase signaling.</p>","PeriodicalId":305851,"journal":{"name":"The EMBO Journal","volume":" ","pages":"e111650"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f3/a4/EMBJ-41-e111650.PMC9434084.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40552093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The EMBO JournalPub Date : 2022-09-01Epub Date: 2022-08-02DOI: 10.15252/embj.2022111118
Ábel Vértesy, Oliver L Eichmüller, Julia Naas, Maria Novatchkova, Christopher Esk, Meritxell Balmaña, Sabrina Ladstaetter, Christoph Bock, Arndt von Haeseler, Juergen A Knoblich
{"title":"Gruffi: an algorithm for computational removal of stressed cells from brain organoid transcriptomic datasets.","authors":"Ábel Vértesy, Oliver L Eichmüller, Julia Naas, Maria Novatchkova, Christopher Esk, Meritxell Balmaña, Sabrina Ladstaetter, Christoph Bock, Arndt von Haeseler, Juergen A Knoblich","doi":"10.15252/embj.2022111118","DOIUrl":"https://doi.org/10.15252/embj.2022111118","url":null,"abstract":"<p><p>Organoids enable in vitro modeling of complex developmental processes and disease pathologies. Like most 3D cultures, organoids lack sufficient oxygen supply and therefore experience cellular stress. These negative effects are particularly prominent in complex models, such as brain organoids, and can affect lineage commitment. Here, we analyze brain organoid and fetal single-cell RNA sequencing (scRNAseq) data from published and new datasets, totaling about 190,000 cells. We identify a unique stress signature in the data from all organoid samples, but not in fetal samples. We demonstrate that cell stress is limited to a defined subpopulation of cells that is unique to organoids and does not affect neuronal specification or maturation. We have developed a computational algorithm, Gruffi, which uses granular functional filtering to identify and remove stressed cells from any organoid scRNAseq dataset in an unbiased manner. We validated our method using six additional datasets from different organoid protocols and early brains, and show its usefulness to other organoid systems including retinal organoids. Our data show that the adverse effects of cell stress can be corrected by bioinformatic analysis for improved delineation of developmental trajectories and resemblance to in vivo data.</p>","PeriodicalId":305851,"journal":{"name":"The EMBO Journal","volume":" ","pages":"e111118"},"PeriodicalIF":11.4,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9433936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40665702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The EMBO JournalPub Date : 2022-09-01Epub Date: 2022-07-25DOI: 10.15252/embj.2022111608
Valter Bergant, Shintaro Yamada, Vincent Grass, Yuta Tsukamoto, Teresa Lavacca, Karsten Krey, Maria-Teresa Mühlhofer, Sabine Wittmann, Armin Ensser, Alexandra Herrmann, Anja Vom Hemdt, Yuriko Tomita, Shutoku Matsuyama, Takatsugu Hirokawa, Yiqi Huang, Antonio Piras, Constanze A Jakwerth, Madlen Oelsner, Susanne Thieme, Alexander Graf, Stefan Krebs, Helmut Blum, Beate M Kümmerer, Alexey Stukalov, Carsten B Schmidt-Weber, Manabu Igarashi, Thomas Gramberg, Andreas Pichlmair, Hiroki Kato
{"title":"Attenuation of SARS-CoV-2 replication and associated inflammation by concomitant targeting of viral and host cap 2'-O-ribose methyltransferases.","authors":"Valter Bergant, Shintaro Yamada, Vincent Grass, Yuta Tsukamoto, Teresa Lavacca, Karsten Krey, Maria-Teresa Mühlhofer, Sabine Wittmann, Armin Ensser, Alexandra Herrmann, Anja Vom Hemdt, Yuriko Tomita, Shutoku Matsuyama, Takatsugu Hirokawa, Yiqi Huang, Antonio Piras, Constanze A Jakwerth, Madlen Oelsner, Susanne Thieme, Alexander Graf, Stefan Krebs, Helmut Blum, Beate M Kümmerer, Alexey Stukalov, Carsten B Schmidt-Weber, Manabu Igarashi, Thomas Gramberg, Andreas Pichlmair, Hiroki Kato","doi":"10.15252/embj.2022111608","DOIUrl":"https://doi.org/10.15252/embj.2022111608","url":null,"abstract":"<p><p>The SARS-CoV-2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'-O-ribose cap needed for viral immune escape. We find that the host cap 2'-O-ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS-CoV-2 replication. Using in silico target-based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti-SARS-CoV-2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co-substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro, in ex vivo, and in a mouse infection model and synergizes with existing COVID-19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection-induced hyperinflammation and reduces lung fibrosis markers ex vivo. Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID-19.</p>","PeriodicalId":305851,"journal":{"name":"The EMBO Journal","volume":" ","pages":"e111608"},"PeriodicalIF":11.4,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9350232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40615323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The EMBO JournalPub Date : 2022-08-16Epub Date: 2022-07-12DOI: 10.15252/embj.2021110550
Lizelle Lubbe, Bryan Trevor Sewell, Jeremy D Woodward, Edward D Sturrock
{"title":"Cryo-EM reveals mechanisms of angiotensin I-converting enzyme allostery and dimerization.","authors":"Lizelle Lubbe, Bryan Trevor Sewell, Jeremy D Woodward, Edward D Sturrock","doi":"10.15252/embj.2021110550","DOIUrl":"https://doi.org/10.15252/embj.2021110550","url":null,"abstract":"<p><p>Hypertension (high blood pressure) is a major risk factor for cardiovascular disease, which is the leading cause of death worldwide. The somatic isoform of angiotensin I-converting enzyme (sACE) plays a critical role in blood pressure regulation, and ACE inhibitors are thus widely used to treat hypertension and cardiovascular disease. Our current understanding of sACE structure, dynamics, function, and inhibition has been limited because truncated, minimally glycosylated forms of sACE are typically used for X-ray crystallography and molecular dynamics simulations. Here, we report the first cryo-EM structures of full-length, glycosylated, soluble sACE (sACE<sup>S1211</sup> ). Both monomeric and dimeric forms of the highly flexible apo enzyme were reconstructed from a single dataset. The N- and C-terminal domains of monomeric sACE<sup>S1211</sup> were resolved at 3.7 and 4.1 Å, respectively, while the interacting N-terminal domains responsible for dimer formation were resolved at 3.8 Å. Mechanisms are proposed for intradomain hinging, cooperativity, and homodimerization. Furthermore, the observation that both domains were in the open conformation has implications for the design of sACE modulators.</p>","PeriodicalId":305851,"journal":{"name":"The EMBO Journal","volume":" ","pages":"e110550"},"PeriodicalIF":11.4,"publicationDate":"2022-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9379546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40608393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The EMBO JournalPub Date : 2022-08-16Epub Date: 2022-07-01DOI: 10.15252/embj.2021110527
Caitlin E Hatton, Deborah H Brotherton, Mahalah Spencer, Alexander D Cameron
{"title":"Structure of cytosine transport protein CodB provides insight into nucleobase-cation symporter 1 mechanism.","authors":"Caitlin E Hatton, Deborah H Brotherton, Mahalah Spencer, Alexander D Cameron","doi":"10.15252/embj.2021110527","DOIUrl":"10.15252/embj.2021110527","url":null,"abstract":"<p><p>CodB is a cytosine transporter from the Nucleobase-Cation-Symport-1 (NCS1) transporter family, a member of the widespread LeuT superfamily. Previous experiments with the nosocomial pathogen Pseudomonas aeruginosa have shown CodB as also important for the uptake of 5-fluorocytosine, which has been suggested as a novel drug to combat antimicrobial resistance by suppressing virulence. Here we solve the crystal structure of CodB from Proteus vulgaris, at 2.4 Å resolution in complex with cytosine. We show that CodB carries out the sodium-dependent uptake of cytosine and can bind 5-fluorocytosine. Comparison of the substrate-bound structures of CodB and the hydantoin transporter Mhp1, the only other NCS1 family member for which the structure is known, highlight the importance of the hydrogen bonds that the substrates make with the main chain at the breakpoint in the discontinuous helix, TM6. In contrast to other LeuT superfamily members, neither CodB nor Mhp1 makes specific interactions with residues on TM1. Comparison of the structures provides insight into the intricate mechanisms of how these proteins transport substrates across the plasma membrane.</p>","PeriodicalId":305851,"journal":{"name":"The EMBO Journal","volume":" ","pages":"e110527"},"PeriodicalIF":0.0,"publicationDate":"2022-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9379551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40574615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The EMBO JournalPub Date : 2022-08-16Epub Date: 2022-08-01DOI: 10.15252/embj.2021110476
Maria Patron, Daryna Tarasenko, Hendrik Nolte, Lara Kroczek, Mausumi Ghosh, Yohsuke Ohba, Yvonne Lasarzewski, Zeinab Alsadat Ahmadi, Alfredo Cabrera-Orefice, Akinori Eyiama, Tim Kellermann, Elena I Rugarli, Ulrich Brandt, Michael Meinecke, Thomas Langer
{"title":"Regulation of mitochondrial proteostasis by the proton gradient.","authors":"Maria Patron, Daryna Tarasenko, Hendrik Nolte, Lara Kroczek, Mausumi Ghosh, Yohsuke Ohba, Yvonne Lasarzewski, Zeinab Alsadat Ahmadi, Alfredo Cabrera-Orefice, Akinori Eyiama, Tim Kellermann, Elena I Rugarli, Ulrich Brandt, Michael Meinecke, Thomas Langer","doi":"10.15252/embj.2021110476","DOIUrl":"https://doi.org/10.15252/embj.2021110476","url":null,"abstract":"<p><p>Mitochondria adapt to different energetic demands reshaping their proteome. Mitochondrial proteases are emerging as key regulators of these adaptive processes. Here, we use a multiproteomic approach to demonstrate the regulation of the m-AAA protease AFG3L2 by the mitochondrial proton gradient, coupling mitochondrial protein turnover to the energetic status of mitochondria. We identify TMBIM5 (previously also known as GHITM or MICS1) as a Ca<sup>2+</sup> /H<sup>+</sup> exchanger in the mitochondrial inner membrane, which binds to and inhibits the m-AAA protease. TMBIM5 ensures cell survival and respiration, allowing Ca<sup>2+</sup> efflux from mitochondria and limiting mitochondrial hyperpolarization. Persistent hyperpolarization, however, triggers degradation of TMBIM5 and activation of the m-AAA protease. The m-AAA protease broadly remodels the mitochondrial proteome and mediates the proteolytic breakdown of respiratory complex I to confine ROS production and oxidative damage in hyperpolarized mitochondria. TMBIM5 thus integrates mitochondrial Ca<sup>2+</sup> signaling and the energetic status of mitochondria with protein turnover rates to reshape the mitochondrial proteome and adjust the cellular metabolism.</p>","PeriodicalId":305851,"journal":{"name":"The EMBO Journal","volume":" ","pages":"e110476"},"PeriodicalIF":11.4,"publicationDate":"2022-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9379554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40572476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The EMBO JournalPub Date : 2022-08-16Epub Date: 2022-07-06DOI: 10.15252/embj.2021110501
Kimberly Wolzak, Anna Nölle, Margherita Farina, Truus Em Abbink, Marjo S van der Knaap, Matthijs Verhage, Wiep Scheper
{"title":"Neuron-specific translational control shift ensures proteostatic resilience during ER stress.","authors":"Kimberly Wolzak, Anna Nölle, Margherita Farina, Truus Em Abbink, Marjo S van der Knaap, Matthijs Verhage, Wiep Scheper","doi":"10.15252/embj.2021110501","DOIUrl":"https://doi.org/10.15252/embj.2021110501","url":null,"abstract":"<p><p>Proteostasis is essential for cellular survival and particularly important for highly specialised post-mitotic cells such as neurons. Transient reduction in protein synthesis by protein kinase R-like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. Here, we demonstrate that PERK-deficient neurons, unlike other cell types, fully retain the capacity to control translation during ER stress. We observe rescaling of the ATF4 response, while the reduction in protein synthesis is fully retained. We identify two molecular pathways that jointly drive translational control in PERK-deficient neurons. Haem-regulated inhibitor (HRI) mediates p-eIF2α and the ATF4 response and is complemented by the tRNA cleaving RNase angiogenin (ANG) to reduce protein synthesis. Overall, our study elucidates an intricate back-up mechanism to ascertain translational control during ER stress in neurons that provides a mechanistic explanation for the thus far unresolved observation of neuronal resilience to proteostatic stress.</p>","PeriodicalId":305851,"journal":{"name":"The EMBO Journal","volume":" ","pages":"e110501"},"PeriodicalIF":11.4,"publicationDate":"2022-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/db/f6/EMBJ-41-e110501.PMC9379547.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40574287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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