Pub Date : 2022-06-29DOI: 10.1101/2022.06.28.498006
H. V. Wende, Mounika Gopi, Megan Onyundo, Claudia Medrano, Temiloluwa Adanlawo, G. Brar
Gametogenesis requires packaging of the cellular components needed for the next generation. In budding yeast, this process includes degradation of many mitotically stable proteins, followed by their resynthesis. Here, we show that one such case—Superoxide dismutase 1 (Sod1), a protein that commonly aggregates in human ALS patients—is regulated by an integrated set of events, beginning with the formation of pre-meiotic Sod1 aggregates. This is followed by degradation of a subset of the prior Sod1 pool and clearance of Sod1 aggregates. As degradation progresses, Sod1 protein production is transiently blocked during mid-meiotic stages by transcription of an extended and poorly translated SOD1 mRNA isoform, SOD1LUTI. Expression of SOD1LUTI is induced by the Unfolded Protein Response, and it acts to repress canonical SOD1 mRNA expression. SOD1LUTI is no longer expressed following the meiotic divisions, enabling a resurgence of canonical mRNA and synthesis of new Sod1 protein such that gametes inherit a full complement of this important enzyme that is essential for gamete viability. Altogether, this work reveals meiosis to be an unusual cellular context in which Sod1 levels are tightly regulated. Our findings also suggest that further investigation of Sod1 during yeast gametogenesis could shed light on conserved aspects of its aggregation and degradation that could have implications for our understanding of human disease.
{"title":"Meiotic resetting of the cellular Sod1 pool is driven by protein aggregation, degradation, and transient LUTI-mediated repression","authors":"H. V. Wende, Mounika Gopi, Megan Onyundo, Claudia Medrano, Temiloluwa Adanlawo, G. Brar","doi":"10.1101/2022.06.28.498006","DOIUrl":"https://doi.org/10.1101/2022.06.28.498006","url":null,"abstract":"Gametogenesis requires packaging of the cellular components needed for the next generation. In budding yeast, this process includes degradation of many mitotically stable proteins, followed by their resynthesis. Here, we show that one such case—Superoxide dismutase 1 (Sod1), a protein that commonly aggregates in human ALS patients—is regulated by an integrated set of events, beginning with the formation of pre-meiotic Sod1 aggregates. This is followed by degradation of a subset of the prior Sod1 pool and clearance of Sod1 aggregates. As degradation progresses, Sod1 protein production is transiently blocked during mid-meiotic stages by transcription of an extended and poorly translated SOD1 mRNA isoform, SOD1LUTI. Expression of SOD1LUTI is induced by the Unfolded Protein Response, and it acts to repress canonical SOD1 mRNA expression. SOD1LUTI is no longer expressed following the meiotic divisions, enabling a resurgence of canonical mRNA and synthesis of new Sod1 protein such that gametes inherit a full complement of this important enzyme that is essential for gamete viability. Altogether, this work reveals meiosis to be an unusual cellular context in which Sod1 levels are tightly regulated. Our findings also suggest that further investigation of Sod1 during yeast gametogenesis could shed light on conserved aspects of its aggregation and degradation that could have implications for our understanding of human disease.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"14 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116033089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-06-25DOI: 10.1101/2022.06.23.497320
C. M. van den Berg, Vladimir A. Volkov, Sebastian Schnorrenberg, Ziwen Huang, Kelly E. Stecker, I. Grigoriev, S. Patzke, T. Zimmermann, M. Dogterom, A. Akhmanova
Microtubules are dynamic cytoskeletal polymers, and their organization and stability are tightly regulated by numerous cellular factors. While regulatory proteins controlling formation of interphase microtubule arrays and mitotic spindles have been extensively studied, the biochemical mechanisms responsible for generating stable microtubule cores of centrioles and cilia are poorly understood. Here, we used in vitro reconstitution assays to investigate microtubule-stabilizing properties of CSPP1, a centrosome and cilia-associated protein mutated in the neurodevelopmental ciliopathy Joubert syndrome. We found that CSPP1 preferentially binds to polymerizing microtubule ends that grow slowly or undergo growth perturbations and, in this way, resembles microtubule-stabilizing compounds such as taxanes. Fluorescence microscopy and cryo-electron tomography showed that CSPP1 is deposited in the microtubule lumen and inhibits microtubule growth and shortening through two separate domains. CSPP1 also specifically recognizes and stabilizes damaged microtubule lattices. These data help to explain how CSPP1 regulates elongation and stability of ciliary axonemes and other microtubule-based structures.
{"title":"CSPP1 stabilizes growing microtubule ends and damaged lattices from the luminal side","authors":"C. M. van den Berg, Vladimir A. Volkov, Sebastian Schnorrenberg, Ziwen Huang, Kelly E. Stecker, I. Grigoriev, S. Patzke, T. Zimmermann, M. Dogterom, A. Akhmanova","doi":"10.1101/2022.06.23.497320","DOIUrl":"https://doi.org/10.1101/2022.06.23.497320","url":null,"abstract":"Microtubules are dynamic cytoskeletal polymers, and their organization and stability are tightly regulated by numerous cellular factors. While regulatory proteins controlling formation of interphase microtubule arrays and mitotic spindles have been extensively studied, the biochemical mechanisms responsible for generating stable microtubule cores of centrioles and cilia are poorly understood. Here, we used in vitro reconstitution assays to investigate microtubule-stabilizing properties of CSPP1, a centrosome and cilia-associated protein mutated in the neurodevelopmental ciliopathy Joubert syndrome. We found that CSPP1 preferentially binds to polymerizing microtubule ends that grow slowly or undergo growth perturbations and, in this way, resembles microtubule-stabilizing compounds such as taxanes. Fluorescence microscopy and cryo-electron tomography showed that CSPP1 is deposited in the microtubule lumen and inhibits microtubule growth and shortening through two separate domains. CSPP1 also specifically recognizes and stabilizes damaged microtubule lattices. These data help to explain how CSPP1 regulates elongation and stability of ciliary axonemes and other microtubule-based structures.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"32 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126852101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ani Michaud, M. Leda, Zachary T. Swider, Songeun Kim, Jiaye He, Jennifer Landino, Jenna R Valley, J. Huisken, A. Goryachev, G. von Dassow, W. Bement
Michaud et al. identify Ect2 and RGA-3/4 as core components of the cortical excitability circuit associated with cytokinesis. Additionally, they demonstrate that the immature Xenopus oocyte is a powerful model for characterizing excitable dynamics.
{"title":"A versatile cortical pattern-forming circuit based on Rho, F-actin, Ect2, and RGA-3/4","authors":"Ani Michaud, M. Leda, Zachary T. Swider, Songeun Kim, Jiaye He, Jennifer Landino, Jenna R Valley, J. Huisken, A. Goryachev, G. von Dassow, W. Bement","doi":"10.1083/jcb.202203017","DOIUrl":"https://doi.org/10.1083/jcb.202203017","url":null,"abstract":"Michaud et al. identify Ect2 and RGA-3/4 as core components of the cortical excitability circuit associated with cytokinesis. Additionally, they demonstrate that the immature Xenopus oocyte is a powerful model for characterizing excitable dynamics.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"33 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122667627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liying Wang, Chao Liu, Bo Yang, Haotian Zhang, J. Jiao, Ruidan Zhang, Shujun Liu, Sai Xiao, Yinghong Chen, Bo Liu, Yanjie Ma, Xuefeng Duan, Yueshuai Guo, Mengmeng Guo, Bingbing Wu, Xiangdong Wang, Xingxu Huang, Haitao Yang, Yaoting Gui, Min Fang, Luo Zhang, Shuguang Duo, Xuejiang Guo, Wei Li
Wang et al. report that the SARS-CoV-2 ORF10 promotes IFT46 degradation via stimulating CUL2ZYG11B activity, thereby impairing both cilia biogenesis and maintenance. The study provides a pathological mechanism connecting COVID-19 symptoms with cilia dysfunction.
Pub Date : 2022-06-04DOI: 10.1101/2022.06.03.494723
R. Chakrabarti, Tak Shun Fung, Taewook Kang, Pieti W. Pallijeff, A. Suomalainen, E. Usherwood, H. Higgs
Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating rapid responses. One rapid response is peri-mitochondrial actin polymerization, termed ADA (acute damage-induced actin). The consequences of ADA are not fully understood. Here we show that ADA is necessary for rapid glycolytic activation upon inhibition of mitochondrial ATP production in multiple cells, including mouse embryonic fibroblasts and effector CD8+ T lymphocytes, for which glycolysis is an important source of ATP and biosynthetic molecules. Treatments that induce ADA include CCCP, antimycin A, rotenone, oligomycin, and hypoxia. The Arp2/3 complex inhibitor CK666 or the mitochondrial sodium-calcium exchanger (NCLX) inhibitor CGP37157, applied simultaneously with the ADA stimulus, inhibit both ADA and the glycolytic increase within 5-min, suggesting that ADA is necessary for glycolytic stimulation. Two situations causing chronic reductions in mitochondrial ATP production, ethidium bromide treatment (to deplete mitochondrial DNA) and mutation to the NDUFS4 subunit of complex 1 of the electron transport chain, cause persistent peri-mitochondrial actin filaments of similar morphology to ADA. Both peri-mitochondrial actin loss and a 20% ATP decrease occur within 10 min of CK666 treatment in NDUFS4 knock-out cells. We propose that ADA is necessary for rapid glycolytic activation upon mitochondrial impairment, to re-establish ATP production.
{"title":"Mitochondrial dysfunction triggers actin polymerization necessary for rapid glycolytic activation","authors":"R. Chakrabarti, Tak Shun Fung, Taewook Kang, Pieti W. Pallijeff, A. Suomalainen, E. Usherwood, H. Higgs","doi":"10.1101/2022.06.03.494723","DOIUrl":"https://doi.org/10.1101/2022.06.03.494723","url":null,"abstract":"Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating rapid responses. One rapid response is peri-mitochondrial actin polymerization, termed ADA (acute damage-induced actin). The consequences of ADA are not fully understood. Here we show that ADA is necessary for rapid glycolytic activation upon inhibition of mitochondrial ATP production in multiple cells, including mouse embryonic fibroblasts and effector CD8+ T lymphocytes, for which glycolysis is an important source of ATP and biosynthetic molecules. Treatments that induce ADA include CCCP, antimycin A, rotenone, oligomycin, and hypoxia. The Arp2/3 complex inhibitor CK666 or the mitochondrial sodium-calcium exchanger (NCLX) inhibitor CGP37157, applied simultaneously with the ADA stimulus, inhibit both ADA and the glycolytic increase within 5-min, suggesting that ADA is necessary for glycolytic stimulation. Two situations causing chronic reductions in mitochondrial ATP production, ethidium bromide treatment (to deplete mitochondrial DNA) and mutation to the NDUFS4 subunit of complex 1 of the electron transport chain, cause persistent peri-mitochondrial actin filaments of similar morphology to ADA. Both peri-mitochondrial actin loss and a 20% ATP decrease occur within 10 min of CK666 treatment in NDUFS4 knock-out cells. We propose that ADA is necessary for rapid glycolytic activation upon mitochondrial impairment, to re-establish ATP production.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"35 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123514359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-06-03DOI: 10.1101/2022.06.02.494516
Sacnicte Ramirez-Rios, Sung Ryul Choi, Chadni Sanyal, T. Blum, C. Bosc, Fatma Krichen, E. Denarier, J. Soleilhac, Béatrice Blot, C. Janke, V. Stoppin-Mellet, M. Magiera, I. Arnal, M. Steinmetz, M. Moutin
The detyrosination/tyrosination cycle of α-tubulin is critical for proper cell functioning. VASH1-SVBP and VASH2-SVBP are ubiquitous enzyme complexes involved in microtubule detyrosination. However, little is known about their mode of action. Here, we show in reconstituted systems and in cells that VASH1-SVBP and VASH2-SVBP drive global and local detyrosination of microtubules, respectively. We solved the cryo-electron microscopy structure of human VASH2-SVBP bound to microtubules, revealing a different microtubule-binding configuration of its central catalytic region compared to VASH1-SVBP. We further show that the divergent mode of detyrosination between the two enzymes is correlated with the microtubule-binding properties of their disordered N- and C-terminal regions. Specifically, the N-terminal region is responsible for a significantly longer residence time of VASH2-SVBP on microtubules compared to VASH1-SVBP. We suggest that this VASH domain is critical for microtubule-detachment and diffusion of VASH-SVBP enzymes on the lattice. Together, our results suggest a mechanism by which these enzymes could generate distinct microtubule subpopulations and confined areas of detyrosinated lattices to drive various microtubule-based cellular functions. SUMMARY VASH1-SVBP and VASH2-SVBP produce global and local detyrosination patterns of microtubule lattices, respectively. These activities rely on the interplay between the N- and C-terminal disordered regions of the enzymes, which determine their differential molecular mechanism of action. GRAPHICAL ABSTRACT Schematic representation of divergent molecular mechanisms of action of VASH-SVBP detyrosination complexes.
{"title":"VASH1–SVBP and VASH2–SVBP generate different detyrosination profiles on microtubules","authors":"Sacnicte Ramirez-Rios, Sung Ryul Choi, Chadni Sanyal, T. Blum, C. Bosc, Fatma Krichen, E. Denarier, J. Soleilhac, Béatrice Blot, C. Janke, V. Stoppin-Mellet, M. Magiera, I. Arnal, M. Steinmetz, M. Moutin","doi":"10.1101/2022.06.02.494516","DOIUrl":"https://doi.org/10.1101/2022.06.02.494516","url":null,"abstract":"The detyrosination/tyrosination cycle of α-tubulin is critical for proper cell functioning. VASH1-SVBP and VASH2-SVBP are ubiquitous enzyme complexes involved in microtubule detyrosination. However, little is known about their mode of action. Here, we show in reconstituted systems and in cells that VASH1-SVBP and VASH2-SVBP drive global and local detyrosination of microtubules, respectively. We solved the cryo-electron microscopy structure of human VASH2-SVBP bound to microtubules, revealing a different microtubule-binding configuration of its central catalytic region compared to VASH1-SVBP. We further show that the divergent mode of detyrosination between the two enzymes is correlated with the microtubule-binding properties of their disordered N- and C-terminal regions. Specifically, the N-terminal region is responsible for a significantly longer residence time of VASH2-SVBP on microtubules compared to VASH1-SVBP. We suggest that this VASH domain is critical for microtubule-detachment and diffusion of VASH-SVBP enzymes on the lattice. Together, our results suggest a mechanism by which these enzymes could generate distinct microtubule subpopulations and confined areas of detyrosinated lattices to drive various microtubule-based cellular functions. SUMMARY VASH1-SVBP and VASH2-SVBP produce global and local detyrosination patterns of microtubule lattices, respectively. These activities rely on the interplay between the N- and C-terminal disordered regions of the enzymes, which determine their differential molecular mechanism of action. GRAPHICAL ABSTRACT Schematic representation of divergent molecular mechanisms of action of VASH-SVBP detyrosination complexes.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"404 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116075849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thoru Pederson discusses the life and achievements of Sheldon Penman, who passed away on September 27, 2021.
索尔·佩德森讨论了谢尔登·彭曼的生活和成就，他于2021年9月27日去世。
{"title":"Sheldon Penman: Visionary of cell form and function","authors":"T. Pederson","doi":"10.1083/jcb.202205033","DOIUrl":"https://doi.org/10.1083/jcb.202205033","url":null,"abstract":"Thoru Pederson discusses the life and achievements of Sheldon Penman, who passed away on September 27, 2021.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"221 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130973856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sara Wickström combines biophysics, next-generation sequencing, and basic cell biology to investigate how cellular forces regulate the fate and position of stem cells within epithelial tissues.
Sara Wickström结合生物物理学，下一代测序和基本细胞生物学来研究细胞力量如何调节上皮组织内干细胞的命运和位置。
{"title":"Sara Wickström: The forces controlling our cell fate","authors":"Lucia Morgado-Palacin","doi":"10.1083/jcb.202205077","DOIUrl":"https://doi.org/10.1083/jcb.202205077","url":null,"abstract":"Sara Wickström combines biophysics, next-generation sequencing, and basic cell biology to investigate how cellular forces regulate the fate and position of stem cells within epithelial tissues.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125878637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ákos Farkas, H. Urlaub, K. Bohnsack, B. Schwappach
Farkas et al. identify monotopic hairpin proteins as novel clients of the guided entry of tail-anchored proteins (GET) pathway. They demonstrate that high efficiency GET pathway–mediated ER targeting of the budding yeast hairpin protein Erg1, a key enzyme of sterol synthesis, becomes essential under conditions requiring increased Erg1 biogenetic flux.
{"title":"Regulated targeting of the monotopic hairpin membrane protein Erg1 requires the GET pathway","authors":"Ákos Farkas, H. Urlaub, K. Bohnsack, B. Schwappach","doi":"10.1083/jcb.202201036","DOIUrl":"https://doi.org/10.1083/jcb.202201036","url":null,"abstract":"Farkas et al. identify monotopic hairpin proteins as novel clients of the guided entry of tail-anchored proteins (GET) pathway. They demonstrate that high efficiency GET pathway–mediated ER targeting of the budding yeast hairpin protein Erg1, a key enzyme of sterol synthesis, becomes essential under conditions requiring increased Erg1 biogenetic flux.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"29 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125247270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis","authors":"E. Eskandari, C. Eaves","doi":"10.1083/jcb.202201159","DOIUrl":"https://doi.org/10.1083/jcb.202201159","url":null,"abstract":"Eskandari and Eaves review evidence of caspase-3-regulated protein quality, proliferation, differentiation, and tumorigenic activity in viable cells.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"65 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114845285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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