Jiajia Wang, Lijun Yang, Yiwen Du, Jincheng Wang, Qinjie Weng, Xuezhao Liu, Eva Nicholson, Mei Xin, Q. R. Lu
Chromatin-remodeling protein BRG1/SMARCA4 is pivotal for establishing oligodendrocyte (OL) lineage identity. However, its functions for oligodendrocyte-precursor cell (OPC) differentiation within the postnatal brain and during remyelination remain elusive. Here, we demonstrate that Brg1 loss profoundly impairs OPC differentiation in the brain with a comparatively lesser effect in the spinal cord. Moreover, BRG1 is critical for OPC remyelination after injury. Integrative transcriptomic/genomic profiling reveals that BRG1 exhibits a dual role by promoting OPC differentiation networks while repressing OL-inhibitory cues and proneuronal programs. Furthermore, we find that BRG1 interacts with EED/PRC2 polycomb-repressive-complexes to enhance H3K27me3-mediated repression at gene loci associated with OL-differentiation inhibition and neurogenesis. Notably, BRG1 depletion decreases H3K27me3 deposition, leading to the upregulation of BMP/WNT signaling and proneurogenic genes, which suppresses OL programs. Thus, our findings reveal a hitherto unexplored spatiotemporal-specific role of BRG1 for OPC differentiation in the developing CNS and underscore a new insight into BRG1/PRC2-mediated epigenetic regulation that promotes and safeguards OL lineage commitment and differentiation.
{"title":"BRG1 programs PRC2-complex repression and controls oligodendrocyte differentiation and remyelination.","authors":"Jiajia Wang, Lijun Yang, Yiwen Du, Jincheng Wang, Qinjie Weng, Xuezhao Liu, Eva Nicholson, Mei Xin, Q. R. Lu","doi":"10.1083/jcb.202310143","DOIUrl":"https://doi.org/10.1083/jcb.202310143","url":null,"abstract":"Chromatin-remodeling protein BRG1/SMARCA4 is pivotal for establishing oligodendrocyte (OL) lineage identity. However, its functions for oligodendrocyte-precursor cell (OPC) differentiation within the postnatal brain and during remyelination remain elusive. Here, we demonstrate that Brg1 loss profoundly impairs OPC differentiation in the brain with a comparatively lesser effect in the spinal cord. Moreover, BRG1 is critical for OPC remyelination after injury. Integrative transcriptomic/genomic profiling reveals that BRG1 exhibits a dual role by promoting OPC differentiation networks while repressing OL-inhibitory cues and proneuronal programs. Furthermore, we find that BRG1 interacts with EED/PRC2 polycomb-repressive-complexes to enhance H3K27me3-mediated repression at gene loci associated with OL-differentiation inhibition and neurogenesis. Notably, BRG1 depletion decreases H3K27me3 deposition, leading to the upregulation of BMP/WNT signaling and proneurogenic genes, which suppresses OL programs. Thus, our findings reveal a hitherto unexplored spatiotemporal-specific role of BRG1 for OPC differentiation in the developing CNS and underscore a new insight into BRG1/PRC2-mediated epigenetic regulation that promotes and safeguards OL lineage commitment and differentiation.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"100 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140669858","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}
The regulation of intracellular membrane traffic is coupled with the cell's need to respond to environmental stimuli, which ultimately is critical for different processes such as cell growth and development. In this issue, Wiese et al. (https://www.doi.org/10.1083/jcb.202311125) explore the role of the trans-Golgi network (TGN) in stress response, exposing its role in mediating adaptive growth decisions.
{"title":"Unveiling the TRAPP: The role of plant TRAPPII in adaptive growth decisions.","authors":"Antonio Galindo","doi":"10.1083/jcb.202404039","DOIUrl":"https://doi.org/10.1083/jcb.202404039","url":null,"abstract":"The regulation of intracellular membrane traffic is coupled with the cell's need to respond to environmental stimuli, which ultimately is critical for different processes such as cell growth and development. In this issue, Wiese et al. (https://www.doi.org/10.1083/jcb.202311125) explore the role of the trans-Golgi network (TGN) in stress response, exposing its role in mediating adaptive growth decisions.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"10 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140671335","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}
Yongrong Liao, Leonid Andronov, Xiaotian Liu, Junyan Lin, Lucile Guerber, Linjie Lu, Arantxa Agote-Arán, Evanthia Pangou, Li Ran, Charlotte Kleiss, Mengdi Qu, Stephane Schmucker, Luca Cirillo, Zhirong Zhang, Daniel Riveline, M. Gotta, B. Klaholz, I. Sumara
Yongrong Liao et al. show how UBAP2L facilitates assembly and stability of mature NPCs at the nuclear envelope during early interphase to ensure efficient nuclear transport, adaptation to nutrient stress, and cellular proliferative capacity of human cells.
{"title":"UBAP2L ensures homeostasis of nuclear pore complexes at the intact nuclear envelope","authors":"Yongrong Liao, Leonid Andronov, Xiaotian Liu, Junyan Lin, Lucile Guerber, Linjie Lu, Arantxa Agote-Arán, Evanthia Pangou, Li Ran, Charlotte Kleiss, Mengdi Qu, Stephane Schmucker, Luca Cirillo, Zhirong Zhang, Daniel Riveline, M. Gotta, B. Klaholz, I. Sumara","doi":"10.1083/jcb.202310006","DOIUrl":"https://doi.org/10.1083/jcb.202310006","url":null,"abstract":"Yongrong Liao et al. show how UBAP2L facilitates assembly and stability of mature NPCs at the nuclear envelope during early interphase to ensure efficient nuclear transport, adaptation to nutrient stress, and cellular proliferative capacity of human cells.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"118 33","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140669602","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}
Migrasomes, organelles crucial for cell communication, undergo distinct stages of nucleation, maturation, and expansion. The regulatory mechanisms of migrasome formation, particularly through biological cues, remain largely unexplored. This study reveals that calcium is essential for migrasome formation. Furthermore, we identify that Synaptotagmin-1 (Syt1), a well-known calcium sensor, is not only enriched in migrasomes but also indispensable for their formation. The calcium-binding ability of Syt1 is key to initiating migrasome formation. The recruitment of Syt1 to migrasome formation sites (MFS) triggers the swelling of MFS into unstable precursors, which are subsequently stabilized through the sequential recruitment of tetraspanins. Our findings reveal how calcium regulates migrasome formation and propose a sequential interaction model involving Syt1 and Tetraspanins in the formation and stabilization of migrasomes.
{"title":"Calcium ions promote migrasome formation via Synaptotagmin-1.","authors":"Yiyang Han, Li Yu","doi":"10.1083/jcb.202402060","DOIUrl":"https://doi.org/10.1083/jcb.202402060","url":null,"abstract":"Migrasomes, organelles crucial for cell communication, undergo distinct stages of nucleation, maturation, and expansion. The regulatory mechanisms of migrasome formation, particularly through biological cues, remain largely unexplored. This study reveals that calcium is essential for migrasome formation. Furthermore, we identify that Synaptotagmin-1 (Syt1), a well-known calcium sensor, is not only enriched in migrasomes but also indispensable for their formation. The calcium-binding ability of Syt1 is key to initiating migrasome formation. The recruitment of Syt1 to migrasome formation sites (MFS) triggers the swelling of MFS into unstable precursors, which are subsequently stabilized through the sequential recruitment of tetraspanins. Our findings reveal how calcium regulates migrasome formation and propose a sequential interaction model involving Syt1 and Tetraspanins in the formation and stabilization of migrasomes.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"93 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140677097","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}
Yung-Li Chen, Alisha N Jones, Amy Crawford, Michael Sattler, Andreas Ettinger, M. Torres-Padilla
The centromere is a fundamental higher-order structure in chromosomes ensuring their faithful segregation upon cell division. Centromeric transcripts have been described in several species and suggested to participate in centromere function. However, low sequence conservation of centromeric repeats appears inconsistent with a role in recruiting highly conserved centromeric proteins. Here, we hypothesized that centromeric transcripts may function through a secondary structure rather than sequence conservation. Using mouse embryonic stem cells (ESCs), we show that an imbalance in the levels of forward or reverse minor satellite (MinSat) transcripts leads to severe chromosome segregation defects. We further show that MinSat RNA adopts a stem-loop secondary structure, which is conserved in human α-satellite transcripts. We identify an RNA binding region in CENPC and demonstrate that MinSat transcripts function through the structured region of the RNA. Importantly, mutants that disrupt MinSat secondary structure do not cause segregation defects. We propose that the conserved role of centromeric transcripts relies on their secondary RNA structure.
{"title":"Determinants of minor satellite RNA function in chromosome segregation in mouse embryonic stem cells.","authors":"Yung-Li Chen, Alisha N Jones, Amy Crawford, Michael Sattler, Andreas Ettinger, M. Torres-Padilla","doi":"10.1083/jcb.202309027","DOIUrl":"https://doi.org/10.1083/jcb.202309027","url":null,"abstract":"The centromere is a fundamental higher-order structure in chromosomes ensuring their faithful segregation upon cell division. Centromeric transcripts have been described in several species and suggested to participate in centromere function. However, low sequence conservation of centromeric repeats appears inconsistent with a role in recruiting highly conserved centromeric proteins. Here, we hypothesized that centromeric transcripts may function through a secondary structure rather than sequence conservation. Using mouse embryonic stem cells (ESCs), we show that an imbalance in the levels of forward or reverse minor satellite (MinSat) transcripts leads to severe chromosome segregation defects. We further show that MinSat RNA adopts a stem-loop secondary structure, which is conserved in human α-satellite transcripts. We identify an RNA binding region in CENPC and demonstrate that MinSat transcripts function through the structured region of the RNA. Importantly, mutants that disrupt MinSat secondary structure do not cause segregation defects. We propose that the conserved role of centromeric transcripts relies on their secondary RNA structure.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140698624","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}
Using an engineered mitochondrial clogger, Krakowczyk et al. (https://doi.org/10.1083/jcb.202306051) identified the OMA1 protease as a critical component that eliminates import failure at the TOM translocase in mammalian cells, providing a novel quality control mechanism that is distinct from those described in yeast.
Krakowczyk 等人（https://doi.org/10.1083/jcb.202306051）利用改造的线粒体堵塞器，发现 OMA1 蛋白酶是哺乳动物细胞中消除 TOM 易位酶导入失败的关键部件，提供了一种有别于酵母的新型质量控制机制。
{"title":"OMA1 clears traffic jam in TOM tunnel in mammals.","authors":"Shiori Sekine, Yusuke Sekine","doi":"10.1083/jcb.202403190","DOIUrl":"https://doi.org/10.1083/jcb.202403190","url":null,"abstract":"Using an engineered mitochondrial clogger, Krakowczyk et al. (https://doi.org/10.1083/jcb.202306051) identified the OMA1 protease as a critical component that eliminates import failure at the TOM translocase in mammalian cells, providing a novel quality control mechanism that is distinct from those described in yeast.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140701161","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}
Meng Li, Yali Hou, Yuzheng Zhou, Zhenni Yang, Hongyu Zhao, Tao Jian, Qianxi Yu, Fuxing Zeng, Xiaotian Liu, Zheng Zhang, Yan G Zhao
β-Coronaviruses remodel host endomembranes to form double-membrane vesicles (DMVs) as replication organelles (ROs) that provide a shielded microenvironment for viral RNA synthesis in infected cells. DMVs are clustered, but the molecular underpinnings and pathophysiological functions remain unknown. Here, we reveal that host fragile X-related (FXR) family proteins (FXR1/FXR2/FMR1) are required for DMV clustering induced by expression of viral non-structural proteins (Nsps) Nsp3 and Nsp4. Depleting FXRs results in DMV dispersion in the cytoplasm. FXR1/2 and FMR1 are recruited to DMV sites via specific interaction with Nsp3. FXRs form condensates driven by liquid-liquid phase separation, which is required for DMV clustering. FXR1 liquid droplets concentrate Nsp3 and Nsp3-decorated liposomes in vitro. FXR droplets facilitate recruitment of translation machinery for efficient translation surrounding DMVs. In cells depleted of FXRs, SARS-CoV-2 replication is significantly attenuated. Thus, SARS-CoV-2 exploits host FXR proteins to cluster viral DMVs via phase separation for efficient viral replication.
{"title":"LLPS of FXR proteins drives replication organelle clustering for β-coronaviral proliferation.","authors":"Meng Li, Yali Hou, Yuzheng Zhou, Zhenni Yang, Hongyu Zhao, Tao Jian, Qianxi Yu, Fuxing Zeng, Xiaotian Liu, Zheng Zhang, Yan G Zhao","doi":"10.1083/jcb.202309140","DOIUrl":"https://doi.org/10.1083/jcb.202309140","url":null,"abstract":"β-Coronaviruses remodel host endomembranes to form double-membrane vesicles (DMVs) as replication organelles (ROs) that provide a shielded microenvironment for viral RNA synthesis in infected cells. DMVs are clustered, but the molecular underpinnings and pathophysiological functions remain unknown. Here, we reveal that host fragile X-related (FXR) family proteins (FXR1/FXR2/FMR1) are required for DMV clustering induced by expression of viral non-structural proteins (Nsps) Nsp3 and Nsp4. Depleting FXRs results in DMV dispersion in the cytoplasm. FXR1/2 and FMR1 are recruited to DMV sites via specific interaction with Nsp3. FXRs form condensates driven by liquid-liquid phase separation, which is required for DMV clustering. FXR1 liquid droplets concentrate Nsp3 and Nsp3-decorated liposomes in vitro. FXR droplets facilitate recruitment of translation machinery for efficient translation surrounding DMVs. In cells depleted of FXRs, SARS-CoV-2 replication is significantly attenuated. Thus, SARS-CoV-2 exploits host FXR proteins to cluster viral DMVs via phase separation for efficient viral replication.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"22 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140728403","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}
Akshay Hegde, Subhasri Ghosh, Akhil Shp Ananthan, Sunny Kataria, Abhik Dutta, Srilekha Prabhu, S. Khedkar, A. Dutta, Colin Jamora
The wound-healing process is a paradigm of the directed migration of various pools of stem cells from their niche to the site of injury where they replenish damaged cells. Two decades have elapsed since the observation that wounding activates multipotent hair follicle stem cells to infiltrate the epidermis, but the cues that coax these cells out of their niche remain unknown. Here, we report that Caspase-1, a protein classically known as an integral component of the cytosolic inflammasome, is secreted upon wounding and has a non-canonical role in the extracellular milieu. Through its caspase activation recruitment domain (CARD), Caspase-1 is sufficient to initiate the migration of hair follicle stem cells into the epidermis. Uncovering this novel function of Caspase-1 also facilitates a deeper understanding of the mechanistic basis of the epithelial hyperplasia found to accompany numerous inflammatory skin diseases.
{"title":"Extracellular Caspase-1 induces hair stem cell migration in wounded and inflamed skin conditions.","authors":"Akshay Hegde, Subhasri Ghosh, Akhil Shp Ananthan, Sunny Kataria, Abhik Dutta, Srilekha Prabhu, S. Khedkar, A. Dutta, Colin Jamora","doi":"10.1083/jcb.202306028","DOIUrl":"https://doi.org/10.1083/jcb.202306028","url":null,"abstract":"The wound-healing process is a paradigm of the directed migration of various pools of stem cells from their niche to the site of injury where they replenish damaged cells. Two decades have elapsed since the observation that wounding activates multipotent hair follicle stem cells to infiltrate the epidermis, but the cues that coax these cells out of their niche remain unknown. Here, we report that Caspase-1, a protein classically known as an integral component of the cytosolic inflammasome, is secreted upon wounding and has a non-canonical role in the extracellular milieu. Through its caspase activation recruitment domain (CARD), Caspase-1 is sufficient to initiate the migration of hair follicle stem cells into the epidermis. Uncovering this novel function of Caspase-1 also facilitates a deeper understanding of the mechanistic basis of the epithelial hyperplasia found to accompany numerous inflammatory skin diseases.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"27 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140732177","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}
M. S. Robinson, Robin Antrobus, Anneri Sanger, A. Davies, David C. Gershlick
Robinson et al. investigate AP-1 function using complementary approaches on cells coexpressing tagged AP-1 and cargo proteins. Their results support a model in which AP-1 is recruited onto post-Golgi carriers and early/recycling endosomes, where it retrieves selected proteins back to the TGN.
{"title":"The role of the AP-1 adaptor complex in outgoing and incoming membrane traffic","authors":"M. S. Robinson, Robin Antrobus, Anneri Sanger, A. Davies, David C. Gershlick","doi":"10.1083/jcb.202310071","DOIUrl":"https://doi.org/10.1083/jcb.202310071","url":null,"abstract":"Robinson et al. investigate AP-1 function using complementary approaches on cells coexpressing tagged AP-1 and cargo proteins. Their results support a model in which AP-1 is recruited onto post-Golgi carriers and early/recycling endosomes, where it retrieves selected proteins back to the TGN.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"47 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140736654","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}
Jack Houston, Clémence Vissotsky, Amar Deep, Hiroyuki Hakozaki, Enice Crews, K. Oegema, Kevin D. Corbett, Pablo Lara-Gonzalez, Taekyung Kim, A. Desai
During mitosis, the Bub1-Bub3 complex concentrates at kinetochores, the microtubule-coupling interfaces on chromosomes, where it contributes to spindle checkpoint activation, kinetochore-spindle microtubule interactions, and protection of centromeric cohesion. Bub1 has a conserved N-terminal tetratricopeptide repeat (TPR) domain followed by a binding motif for its conserved interactor Bub3. The current model for Bub1-Bub3 localization to kinetochores is that Bub3, along with its bound motif from Bub1, recognizes phosphorylated "MELT" motifs in the kinetochore scaffold protein Knl1. Motivated by the greater phenotypic severity of BUB-1 versus BUB-3 loss in C. elegans, we show that the BUB-1 TPR domain directly recognizes a distinct class of phosphorylated motifs in KNL-1 and that this interaction is essential for BUB-1-BUB-3 localization and function. BUB-3 recognition of phospho-MELT motifs additively contributes to drive super-stoichiometric accumulation of BUB-1-BUB-3 on its KNL-1 scaffold during mitotic entry. Bub1's TPR domain interacts with Knl1 in other species, suggesting that collaboration of TPR-dependent and Bub3-dependent interfaces in Bub1-Bub3 localization and functions may be conserved.
{"title":"Phospho-KNL-1 recognition by a TPR domain targets the BUB-1-BUB-3 complex to C. elegans kinetochores.","authors":"Jack Houston, Clémence Vissotsky, Amar Deep, Hiroyuki Hakozaki, Enice Crews, K. Oegema, Kevin D. Corbett, Pablo Lara-Gonzalez, Taekyung Kim, A. Desai","doi":"10.1083/jcb.202402036","DOIUrl":"https://doi.org/10.1083/jcb.202402036","url":null,"abstract":"During mitosis, the Bub1-Bub3 complex concentrates at kinetochores, the microtubule-coupling interfaces on chromosomes, where it contributes to spindle checkpoint activation, kinetochore-spindle microtubule interactions, and protection of centromeric cohesion. Bub1 has a conserved N-terminal tetratricopeptide repeat (TPR) domain followed by a binding motif for its conserved interactor Bub3. The current model for Bub1-Bub3 localization to kinetochores is that Bub3, along with its bound motif from Bub1, recognizes phosphorylated \"MELT\" motifs in the kinetochore scaffold protein Knl1. Motivated by the greater phenotypic severity of BUB-1 versus BUB-3 loss in C. elegans, we show that the BUB-1 TPR domain directly recognizes a distinct class of phosphorylated motifs in KNL-1 and that this interaction is essential for BUB-1-BUB-3 localization and function. BUB-3 recognition of phospho-MELT motifs additively contributes to drive super-stoichiometric accumulation of BUB-1-BUB-3 on its KNL-1 scaffold during mitotic entry. Bub1's TPR domain interacts with Knl1 in other species, suggesting that collaboration of TPR-dependent and Bub3-dependent interfaces in Bub1-Bub3 localization and functions may be conserved.","PeriodicalId":343306,"journal":{"name":"The Journal of Cell Biology","volume":"17 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140739996","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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