Pub Date : 2025-02-06DOI: 10.1016/j.molcel.2025.01.007
Martine A. Collart, Olesya O. Panasenko
The study by Mallik et al.1 tackles the question of protein assembly in living cells, particularly how extensively co-translational assembly occurs and what rules govern the process. It reveals overarching impact of three-dimensional protein structure for defining assembly pathway.
{"title":"Assembly in action: Protein structure orchestrates assembly pathway, and intertwining defines co-translational assembly","authors":"Martine A. Collart, Olesya O. Panasenko","doi":"10.1016/j.molcel.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.007","url":null,"abstract":"The study by Mallik et al.<span><span><sup>1</sup></span></span> tackles the question of protein assembly in living cells, particularly how extensively co-translational assembly occurs and what rules govern the process. It reveals overarching impact of three-dimensional protein structure for defining assembly pathway.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"16 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.molcel.2025.01.015
Emmanuelle Genoyer, Jonathan Wilson, Joshua M. Ames, Caleb Stokes, Dante Moreno, Noa Etzyon, Andrew Oberst, Michael Gale
For many RNA viruses, immunity is triggered when RIG-I-like receptors (RLRs) detect viral RNA. However, only a minority of infected cells undergo innate immune activation. By examining these “first-responder” cells during West Nile virus infection, we found that specific accumulation of antigenomic negative-sense viral RNA (−vRNA) underlies innate immune activation and that RIG-I preferentially interacts with −vRNA. However, flaviviruses sequester −vRNA into membrane-bound replication compartments away from cytosolic sensors. We found that single-stranded −vRNA accumulates outside of replication compartments in first-responder cells, rendering it accessible to RLRs. Exposure of this −vRNA occurs at late time points of infection, is linked to viral assembly, and depends on the expression of viral structural proteins. These findings reveal that, although most infected cells replicate high levels of vRNA, release of −vRNA from replication compartments during assembly occurs at low frequency and is critical for initiation of innate immunity during flavivirus infection.
{"title":"Exposure of negative-sense viral RNA in the cytoplasm initiates innate immunity to West Nile virus","authors":"Emmanuelle Genoyer, Jonathan Wilson, Joshua M. Ames, Caleb Stokes, Dante Moreno, Noa Etzyon, Andrew Oberst, Michael Gale","doi":"10.1016/j.molcel.2025.01.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.015","url":null,"abstract":"For many RNA viruses, immunity is triggered when RIG-I-like receptors (RLRs) detect viral RNA. However, only a minority of infected cells undergo innate immune activation. By examining these “first-responder” cells during West Nile virus infection, we found that specific accumulation of antigenomic negative-sense viral RNA (−vRNA) underlies innate immune activation and that RIG-I preferentially interacts with −vRNA. However, flaviviruses sequester −vRNA into membrane-bound replication compartments away from cytosolic sensors. We found that single-stranded −vRNA accumulates outside of replication compartments in first-responder cells, rendering it accessible to RLRs. Exposure of this −vRNA occurs at late time points of infection, is linked to viral assembly, and depends on the expression of viral structural proteins. These findings reveal that, although most infected cells replicate high levels of vRNA, release of −vRNA from replication compartments during assembly occurs at low frequency and is critical for initiation of innate immunity during flavivirus infection.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"46 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.molcel.2025.01.005
Alma Sophia Barisaac, Enas R. Abu-Zhayia, Nabieh Ayoub
Metabolite microenvironment shapes cancer treatment strategies. In a recent paper in Nature, Jin et al.1 demonstrate that valine deprivation triggers HDAC6 entry into the nucleus, leading to accumulation of DNA damage that could be harnessed for targeted cancer therapy.
代谢物微环境塑造了癌症治疗策略。在最近发表于《自然》（Nature）的一篇论文中，Jin 等人1 证明，缬氨酸缺乏会触发 HDAC6 进入细胞核，导致 DNA 损伤积累，从而可用于癌症靶向治疗。
{"title":"Leveraging valine-restriction-induced DNA damage for targeted cancer therapy","authors":"Alma Sophia Barisaac, Enas R. Abu-Zhayia, Nabieh Ayoub","doi":"10.1016/j.molcel.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.005","url":null,"abstract":"Metabolite microenvironment shapes cancer treatment strategies. In a recent paper in <em>Nature</em>, Jin et al.<span><span><sup>1</sup></span></span> demonstrate that valine deprivation triggers HDAC6 entry into the nucleus, leading to accumulation of DNA damage that could be harnessed for targeted cancer therapy.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"9 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Impairment of ribosome biogenesis (RiBi) triggered by inhibition of ribosomal RNA (rRNA) synthesis and processing leads to various biological effects. We report that Schlafen 11 (SLFN11) induces TP53-independent apoptosis through RiBi impairment. Upon replication stress, SLFN11 inhibits rRNA synthesis with RNA polymerase I accumulation and increased chromatin accessibility in the ribosomal DNA (rDNA) genes. SLFN11-dependent RiBi impairment preferentially depletes short-lived proteins, particularly MCL1, leading to apoptosis in response to replication stress. SLFN11’s Walker B motif (E669), DNA-binding site (K652), dephosphorylation site for single-strand DNA binding (S753), and RNase sites (E209/E214) are all required for the SLFN11-mediated RiBi impairment. Comparable effects were obtained with direct RNA polymerase I inhibitors and other RiBi inhibitory conditions regardless of SLFN11. These findings were extended across 34 diverse human cancer cell lines. Thus, we demonstrate that RiBi impairment is a robust inactivator of MCL1 and an additional proapoptotic mechanism by which SLFN11 sensitizes cancer cells to chemotherapeutic agents.
{"title":"SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis","authors":"Akane Ogawa, Keiichi Izumikawa, Sota Tate, Sho Isoyama, Masaru Mori, Kohei Fujiwara, Soyoka Watanabe, Takayuki Ohga, Ukhyun Jo, Daiki Taniyama, Shojiro Kitajima, Soichiro Tanaka, Hiroshi Onji, Shun-Ichiro Kageyama, Gaku Yamamoto, Hitoshi Saito, Tomoko Yamamori Morita, Masayasu Okada, Manabu Natsumeda, Masami Nagahama, Junko Murai","doi":"10.1016/j.molcel.2025.01.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.008","url":null,"abstract":"Impairment of ribosome biogenesis (RiBi) triggered by inhibition of ribosomal RNA (rRNA) synthesis and processing leads to various biological effects. We report that Schlafen 11 (SLFN11) induces TP53-independent apoptosis through RiBi impairment. Upon replication stress, SLFN11 inhibits rRNA synthesis with RNA polymerase I accumulation and increased chromatin accessibility in the ribosomal DNA (rDNA) genes. SLFN11-dependent RiBi impairment preferentially depletes short-lived proteins, particularly MCL1, leading to apoptosis in response to replication stress. SLFN11’s Walker B motif (E669), DNA-binding site (K652), dephosphorylation site for single-strand DNA binding (S753), and RNase sites (E209/E214) are all required for the SLFN11-mediated RiBi impairment. Comparable effects were obtained with direct RNA polymerase I inhibitors and other RiBi inhibitory conditions regardless of SLFN11. These findings were extended across 34 diverse human cancer cell lines. Thus, we demonstrate that RiBi impairment is a robust inactivator of MCL1 and an additional proapoptotic mechanism by which SLFN11 sensitizes cancer cells to chemotherapeutic agents.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"38 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-04DOI: 10.1016/j.molcel.2025.01.029
Sujin Kim, Stephanie Tan, Jayoung Ku, Tria Asri Widowati, Doyeong Ku, Keonyong Lee, Kwontae You, Yoosik Kim
(Molecular Cell 84, 2935–2948.e1–e7; August 8, 2024)
{"title":"RNA 5-methylcytosine marks mitochondrial double-stranded RNAs for degradation and cytosolic release","authors":"Sujin Kim, Stephanie Tan, Jayoung Ku, Tria Asri Widowati, Doyeong Ku, Keonyong Lee, Kwontae You, Yoosik Kim","doi":"10.1016/j.molcel.2025.01.029","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.029","url":null,"abstract":"(Molecular Cell <em>84</em>, 2935–2948.e1–e7; August 8, 2024)","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"40 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-04DOI: 10.1016/j.molcel.2025.01.010
Adrian Bird
Cohesin is a multi-subunit molecular machine that is able to create lateral chromatin loops within a linear chromosome fiber. Despite intense study, a consensus view of the functional significance of loop extrusion has remained elusive. This perspective proposes a rationale based on the need for continual disruption of spurious higher-order chromatin secondary structures. It is argued that cohesin-mediated chromosomal churn ensures broad accessibility to the diffusible factors on which genome function depends.
{"title":"Cohesin as an essential disruptor of chromosome organization","authors":"Adrian Bird","doi":"10.1016/j.molcel.2025.01.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.010","url":null,"abstract":"Cohesin is a multi-subunit molecular machine that is able to create lateral chromatin loops within a linear chromosome fiber. Despite intense study, a consensus view of the functional significance of loop extrusion has remained elusive. This perspective proposes a rationale based on the need for continual disruption of spurious higher-order chromatin secondary structures. It is argued that cohesin-mediated chromosomal churn ensures broad accessibility to the diffusible factors on which genome function depends.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"13 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-31DOI: 10.1016/j.molcel.2025.01.003
Raja H. Ali, Esteban A. Orellana, Su Hyun Lee, Yun-Cheol Chae, Yantao Chen, Jim Clauwaert, Alyssa L. Kennedy, Ashley E. Gutierrez, David J. Papke, Mateo Valenzuela, Brianna Silverman, Amanda Falzetta, Scott B. Ficarro, Jarrod A. Marto, Christopher D.M. Fletcher, Antonio Perez-Atayde, Thierry Alcindor, Akiko Shimamura, John R. Prensner, Richard I. Gregory, Alejandro Gutierrez
Amplification of chromosomal material derived from 12q13-15 is common in human cancer and believed to result in overexpression of multiple collaborating oncogenes. To define the oncogenes involved, we overexpressed genes recurrently amplified in human liposarcoma using a zebrafish model of the disease. We found several genes whose overexpression collaborated with AKT in sarcomagenesis, including the tRNA methyltransferase METTL1. This was surprising, because AKT phosphorylates METTL1 to inactivate its enzymatic activity. Indeed, phosphomimetic S27D or catalytically dead alleles phenocopied the oncogenic activity of wild-type METTL1. We found that METTL1 binds the multi-tRNA synthetase complex, which contains many of the cellular aminoacyl-tRNA synthetases and promotes tRNA aminoacylation, polysome formation, and protein synthesis independent of its methyltransferase activity. METTL1-amplified liposarcomas were hypersensitive to actinomycin D, a clinical inhibitor of ribosome biogenesis. We propose that METTL1 overexpression promotes sarcomagenesis by stimulating tRNA aminoacylation, protein synthesis, and tumor cell growth independent of its methyltransferase activity.
{"title":"A methyltransferase-independent role for METTL1 in tRNA aminoacylation and oncogenic transformation","authors":"Raja H. Ali, Esteban A. Orellana, Su Hyun Lee, Yun-Cheol Chae, Yantao Chen, Jim Clauwaert, Alyssa L. Kennedy, Ashley E. Gutierrez, David J. Papke, Mateo Valenzuela, Brianna Silverman, Amanda Falzetta, Scott B. Ficarro, Jarrod A. Marto, Christopher D.M. Fletcher, Antonio Perez-Atayde, Thierry Alcindor, Akiko Shimamura, John R. Prensner, Richard I. Gregory, Alejandro Gutierrez","doi":"10.1016/j.molcel.2025.01.003","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.003","url":null,"abstract":"Amplification of chromosomal material derived from 12q13-15 is common in human cancer and believed to result in overexpression of multiple collaborating oncogenes. To define the oncogenes involved, we overexpressed genes recurrently amplified in human liposarcoma using a zebrafish model of the disease. We found several genes whose overexpression collaborated with AKT in sarcomagenesis, including the tRNA methyltransferase <em>METTL1</em>. This was surprising, because AKT phosphorylates METTL1 to inactivate its enzymatic activity. Indeed, phosphomimetic S27D or catalytically dead alleles phenocopied the oncogenic activity of wild-type METTL1. We found that METTL1 binds the multi-tRNA synthetase complex, which contains many of the cellular aminoacyl-tRNA synthetases and promotes tRNA aminoacylation, polysome formation, and protein synthesis independent of its methyltransferase activity. METTL1-amplified liposarcomas were hypersensitive to actinomycin D, a clinical inhibitor of ribosome biogenesis. We propose that METTL1 overexpression promotes sarcomagenesis by stimulating tRNA aminoacylation, protein synthesis, and tumor cell growth independent of its methyltransferase activity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"5 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-30DOI: 10.1016/j.molcel.2025.01.004
Emily S. Smith-Pillet, Ramya Billur, Marie-France Langelier, Tanaji T. Talele, John M. Pascal, Ben E. Black
Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 recognize DNA breaks immediately upon their formation, generate a burst of local PARylation to signal their location, and are co-targeted by all current FDA-approved forms of PARP inhibitors (PARPi) used in the cancer clinic. Recent evidence indicates that the same PARPi molecules impact PARP2 differently from PARP1, raising the possibility that allosteric activation may also differ. We find that, unlike for PARP1, destabilization of the autoinhibitory domain of PARP2 is insufficient for DNA damage-induced catalytic activation. Rather, PARP2 activation requires further unfolding of an active site helix. In contrast, the corresponding helix in PARP1 only transiently forms, even prior to engaging DNA. Only one clinical PARPi, Olaparib, stabilizes the PARP2 active site helix, representing a structural feature with the potential to discriminate small molecule inhibitors. Collectively, our findings reveal unanticipated differences in local structure and changes in activation-coupled backbone dynamics between human PARP1 and PARP2.
{"title":"A PARP2 active site helix melts to permit DNA damage-induced enzymatic activation","authors":"Emily S. Smith-Pillet, Ramya Billur, Marie-France Langelier, Tanaji T. Talele, John M. Pascal, Ben E. Black","doi":"10.1016/j.molcel.2025.01.004","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.004","url":null,"abstract":"Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 recognize DNA breaks immediately upon their formation, generate a burst of local PARylation to signal their location, and are co-targeted by all current FDA-approved forms of PARP inhibitors (PARPi) used in the cancer clinic. Recent evidence indicates that the same PARPi molecules impact PARP2 differently from PARP1, raising the possibility that allosteric activation may also differ. We find that, unlike for PARP1, destabilization of the autoinhibitory domain of PARP2 is insufficient for DNA damage-induced catalytic activation. Rather, PARP2 activation requires further unfolding of an active site helix. In contrast, the corresponding helix in PARP1 only transiently forms, even prior to engaging DNA. Only one clinical PARPi, Olaparib, stabilizes the PARP2 active site helix, representing a structural feature with the potential to discriminate small molecule inhibitors. Collectively, our findings reveal unanticipated differences in local structure and changes in activation-coupled backbone dynamics between human PARP1 and PARP2.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"36 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-30DOI: 10.1016/j.molcel.2025.01.006
Wang Jiahui, Yu Xiang, Zhong Youhuan, Ma Xiaomin, Gao Yuanzhu, Zhou Dejian, Wang Jie, Fu Yinkun, Fan Shi, Su Juncheng, Huang Masha, Haigis Marcia, Wang Peiyi, Xu Yingjie, Yang Wen
Mitochondrial heat shock proteins and co-chaperones play crucial roles in maintaining proteostasis by regulating unfolded proteins, usually without specific target preferences. In this study, we identify a DNAJC-type co-chaperone: T cell activation inhibitor, mitochondria (TCAIM), and demonstrate its specific binding to α-ketoglutarate dehydrogenase (OGDH), a key rate-limiting enzyme in mitochondrial metabolism. This interaction suppresses OGDH function and subsequently reduces carbohydrate catabolism in both cultured cells and murine models. Using cryoelectron microscopy (cryo-EM), we resolve the human OGDH-TCAIM complex and reveal that TCAIM binds to OGDH without altering its apo structure. Most importantly, we discover that TCAIM facilitates the reduction of functional OGDH through its interaction, which depends on HSPA9 and LONP1. Our findings unveil a role of the mitochondrial proteostasis system in regulating a critical metabolic enzyme and introduce a previously unrecognized post-translational regulatory mechanism.
{"title":"The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism","authors":"Wang Jiahui, Yu Xiang, Zhong Youhuan, Ma Xiaomin, Gao Yuanzhu, Zhou Dejian, Wang Jie, Fu Yinkun, Fan Shi, Su Juncheng, Huang Masha, Haigis Marcia, Wang Peiyi, Xu Yingjie, Yang Wen","doi":"10.1016/j.molcel.2025.01.006","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.006","url":null,"abstract":"Mitochondrial heat shock proteins and co-chaperones play crucial roles in maintaining proteostasis by regulating unfolded proteins, usually without specific target preferences. In this study, we identify a DNAJC-type co-chaperone: T cell activation inhibitor, mitochondria (TCAIM), and demonstrate its specific binding to α-ketoglutarate dehydrogenase (OGDH), a key rate-limiting enzyme in mitochondrial metabolism. This interaction suppresses OGDH function and subsequently reduces carbohydrate catabolism in both cultured cells and murine models. Using cryoelectron microscopy (cryo-EM), we resolve the human OGDH-TCAIM complex and reveal that TCAIM binds to OGDH without altering its apo structure. Most importantly, we discover that TCAIM facilitates the reduction of functional OGDH through its interaction, which depends on HSPA9 and LONP1. Our findings unveil a role of the mitochondrial proteostasis system in regulating a critical metabolic enzyme and introduce a previously unrecognized post-translational regulatory mechanism.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"29 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1016/j.molcel.2025.01.002
Sara Carrillo Roas, Yuichi Yagita, Paul Murphy, Robert Kurzbauer, Tim Clausen, Eszter Zavodszky, Ramanujan S. Hegde
Unassembled and partially assembled subunits of multi-protein complexes have emerged as major quality control clients, particularly under conditions of imbalanced gene expression such as stress, aging, and aneuploidy. The factors and mechanisms that eliminate such orphan subunits to maintain protein homeostasis are incompletely defined. Here, we show that the UBR4-KCMF1 ubiquitin ligase complex is required for the efficient degradation of multiple unrelated orphan subunits from the chaperonin, proteasome cap, proteasome core, and a protein targeting complex. Epistasis analysis in cells and reconstitution studies in vitro show that the UBR4-KCMF1 complex acts downstream of a priming ubiquitin ligase that first mono-ubiquitinates orphans. UBR4 recognizes both the orphan and its mono-ubiquitin and builds a K48-linked poly-ubiquitin degradation signal. The discovery of a convergence point for multiple quality control pathways may explain why aneuploid cells are especially sensitive to loss of UBR4 or KCMF1 and identifies a potential vulnerability across many cancers.
{"title":"Convergence of orphan quality control pathways at a ubiquitin chain-elongating ligase","authors":"Sara Carrillo Roas, Yuichi Yagita, Paul Murphy, Robert Kurzbauer, Tim Clausen, Eszter Zavodszky, Ramanujan S. Hegde","doi":"10.1016/j.molcel.2025.01.002","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.002","url":null,"abstract":"Unassembled and partially assembled subunits of multi-protein complexes have emerged as major quality control clients, particularly under conditions of imbalanced gene expression such as stress, aging, and aneuploidy. The factors and mechanisms that eliminate such orphan subunits to maintain protein homeostasis are incompletely defined. Here, we show that the UBR4-KCMF1 ubiquitin ligase complex is required for the efficient degradation of multiple unrelated orphan subunits from the chaperonin, proteasome cap, proteasome core, and a protein targeting complex. Epistasis analysis in cells and reconstitution studies <em>in vitro</em> show that the UBR4-KCMF1 complex acts downstream of a priming ubiquitin ligase that first mono-ubiquitinates orphans. UBR4 recognizes both the orphan and its mono-ubiquitin and builds a K48-linked poly-ubiquitin degradation signal. The discovery of a convergence point for multiple quality control pathways may explain why aneuploid cells are especially sensitive to loss of UBR4 or KCMF1 and identifies a potential vulnerability across many cancers.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"7 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：