Molecular Cell最新文献_第2页

mTORC1 activity licenses its own release from the lysosomal surface mTORC1 的活性允许自己从溶酶体表面释放出来

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-31 DOI: 10.1016/j.molcel.2024.10.008

Aishwarya Acharya, Constantinos Demetriades

引用次数: 0

mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes mTORC1 通过自动调节 TFE3 在溶酶体上的存在来限制其活性

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-31 DOI: 10.1016/j.molcel.2024.10.009

Susan Zwakenberg, Denise Westland, Robert M. van Es, Holger Rehmann, Jasper Anink, Jolita Ciapaite, Marjolein Bosma, Ellen Stelloo, Nalan Liv, Paula Sobrevals Alcaraz, Nanda M. Verhoeven-Duif, Judith J.M. Jans, Harmjan R. Vos, Eleonora Aronica, Fried J.T. Zwartkruis

{"title":"mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes","authors":"Susan Zwakenberg, Denise Westland, Robert M. van Es, Holger Rehmann, Jasper Anink, Jolita Ciapaite, Marjolein Bosma, Ellen Stelloo, Nalan Liv, Paula Sobrevals Alcaraz, Nanda M. Verhoeven-Duif, Judith J.M. Jans, Harmjan R. Vos, Eleonora Aronica, Fried J.T. Zwartkruis","doi":"10.1016/j.molcel.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.009","url":null,"abstract":"To stimulate cell growth, the protein kinase complex mTORC1 requires intracellular amino acids for activation. Amino-acid sufficiency is relayed to mTORC1 by Rag GTPases on lysosomes, where growth factor signaling enhances mTORC1 activity via the GTPase Rheb. In the absence of amino acids, GATOR1 inactivates the Rags, resulting in lysosomal detachment and inactivation of mTORC1. We demonstrate that in human cells, the release of mTORC1 from lysosomes depends on its kinase activity. In accordance with a negative feedback mechanism, activated mTOR mutants display low lysosome occupancy, causing hypo-phosphorylation and nuclear localization of the lysosomal substrate TFE3. Surprisingly, mTORC1 activated by Rheb does not increase the cytoplasmic/lysosomal ratio of mTORC1, indicating the existence of mTORC1 pools with distinct substrate specificity. Dysregulation of either pool results in aberrant TFE3 activity and may explain nuclear accumulation of TFE3 in epileptogenic malformations in focal cortical dysplasia type II (FCD II) and tuberous sclerosis (TSC).","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556308","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}

引用次数: 0

Type II topoisomerases shape multi-scale 3D chromatin folding in regions of positive supercoils II 型拓扑异构酶在正超螺旋区域形成多尺度三维染色质折叠

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-31 DOI: 10.1016/j.molcel.2024.10.007

Gabriel M.C. Longo, Sergi Sayols, Maria E. Stefanova, Ting Xie, Waheba Elsayed, Anastasia Panagi, Amalia I. Stavridou, Giuseppe Petrosino, Elizabeth Ing-Simmons, Uirá Souto Melo, Henrike J. Gothe, Juan M. Vaquerizas, Andriana G. Kotini, Argyris Papantonis, Stefan Mundlos, Vassilis Roukos

{"title":"Type II topoisomerases shape multi-scale 3D chromatin folding in regions of positive supercoils","authors":"Gabriel M.C. Longo, Sergi Sayols, Maria E. Stefanova, Ting Xie, Waheba Elsayed, Anastasia Panagi, Amalia I. Stavridou, Giuseppe Petrosino, Elizabeth Ing-Simmons, Uirá Souto Melo, Henrike J. Gothe, Juan M. Vaquerizas, Andriana G. Kotini, Argyris Papantonis, Stefan Mundlos, Vassilis Roukos","doi":"10.1016/j.molcel.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.007","url":null,"abstract":"Type II topoisomerases (TOP2s) resolve torsional stress accumulated during various cellular processes and are enriched at chromatin loop anchors and topologically associated domain (TAD) boundaries, where, when trapped, can lead to genomic instability promoting the formation of oncogenic fusions. Whether TOP2s relieve topological constraints at these positions and/or participate in 3D chromosome folding remains unclear. Here, we combine 3D genomics, imaging, and GapRUN, a method for the genome-wide profiling of positive supercoiling, to assess the role of TOP2s in shaping chromosome organization in human cells. Acute TOP2 depletion led to the emergence of new, large-scale contacts at the boundaries between active, positively supercoiled, and lamina-associated domains. TOP2-dependent changes at the higher-order chromatin folding were accompanied by remodeling of chromatin-nuclear lamina interactions and of gene expression, while at the chromatin loop level, TOP2 depletion predominantly remodeled transcriptionally anchored, positively supercoiled loops. We propose that TOP2s act as a fine regulator of chromosome folding at multiple scales.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556307","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}

引用次数: 0

m6Am sequesters PCF11 to suppress premature termination and drive neuroblastoma differentiation m6Am 可封存 PCF11，从而抑制过早终止并驱动神经母细胞瘤分化

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-30 DOI: 10.1016/j.molcel.2024.10.004

Huihui An, Yifan Hong, Yeek Teck Goh, Casslynn W.Q. Koh, Shahzina Kanwal, Yi Zhang, Zhaoqi Lu, Phoebe M.L. Yap, Suat Peng Neo, Chun-Ming Wong, Alice S.T. Wong, Yang Yu, Jessica Sook Yuin Ho, Jayantha Gunaratne, Wee Siong Sho Goh

{"title":"m6Am sequesters PCF11 to suppress premature termination and drive neuroblastoma differentiation","authors":"Huihui An, Yifan Hong, Yeek Teck Goh, Casslynn W.Q. Koh, Shahzina Kanwal, Yi Zhang, Zhaoqi Lu, Phoebe M.L. Yap, Suat Peng Neo, Chun-Ming Wong, Alice S.T. Wong, Yang Yu, Jessica Sook Yuin Ho, Jayantha Gunaratne, Wee Siong Sho Goh","doi":"10.1016/j.molcel.2024.10.004","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.004","url":null,"abstract":"N6,2′-O-dimethyladenosine (m6Am) is an abundant mRNA modification that impacts multiple diseases, but its function remains controversial because the m6Am reader is unknown. Using quantitative proteomics, we identified transcriptional terminator premature cleavage factor II (PCF11) as a m6Am-specific reader in human cells. Direct quantification of mature versus nascent RNAs reveals that m6Am does not regulate mRNA stability but promotes nascent transcription. Mechanistically, m6Am functions by sequestering PCF11 away from proximal RNA polymerase II (RNA Pol II). This suppresses PCF11 from dissociating RNA Pol II near transcription start sites, thereby promoting full-length transcription of m6Am-modified RNAs. m6Am’s unique relationship with PCF11 means m6Am function is enhanced when PCF11 is reduced, which occurs during all-trans-retinoic-acid (ATRA)-induced neuroblastoma-differentiation therapy. Here, m6Am promotes expression of ATF3, which represses neuroblastoma biomarker MYCN. Depleting m6Am suppresses MYCN repression in ATRA-treated neuroblastoma and maintains their tumor-stem-like properties. Collectively, we characterize m6Am as an anti-terminator RNA modification that suppresses premature termination and modulates neuroblastoma’s therapeutic response.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541584","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}

引用次数: 0

Senescence suppresses the integrated stress response and activates a stress-remodeled secretory phenotype 衰老抑制综合应激反应，激活应激重塑分泌表型

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-30 DOI: 10.1016/j.molcel.2024.10.003

Matthew J. Payea, Showkat A. Dar, Carlos Anerillas, Jennifer L. Martindale, Cedric Belair, Rachel Munk, Sulochan Malla, Jinshui Fan, Yulan Piao, Xiaoling Yang, Abid Rehman, Nirad Banskota, Kotb Abdelmohsen, Myriam Gorospe, Manolis Maragkakis

{"title":"Senescence suppresses the integrated stress response and activates a stress-remodeled secretory phenotype","authors":"Matthew J. Payea, Showkat A. Dar, Carlos Anerillas, Jennifer L. Martindale, Cedric Belair, Rachel Munk, Sulochan Malla, Jinshui Fan, Yulan Piao, Xiaoling Yang, Abid Rehman, Nirad Banskota, Kotb Abdelmohsen, Myriam Gorospe, Manolis Maragkakis","doi":"10.1016/j.molcel.2024.10.003","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.003","url":null,"abstract":"Senescence is a state of indefinite cell-cycle arrest associated with aging, cancer, and age-related diseases. Here, we find that translational deregulation, together with a corresponding maladaptive integrated stress response (ISR), is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response activating transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames (uORFs). Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. We also find that stress augments the senescence-associated secretory phenotype with sustained remodeling of inflammatory factors expression that is suppressed by non-uORF carrying ATF4 mRNA expression. Our results thus show that senescent cells possess a unique response to stress, which entails an increase in their inflammatory profile.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541580","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}

引用次数: 0

COLD6-OSM1 module senses chilling for cold tolerance via 2′,3′-cAMP signaling in rice 水稻中的 COLD6-OSM1 模块通过 2′,3′-cAMP 信号传导感知寒冷以提高耐寒性

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-30 DOI: 10.1016/j.molcel.2024.09.031

Wei Luo, Yunyuan Xu, Jie Cao, Xiaoyu Guo, Jingdan Han, Yuanyuan Zhang, Yuda Niu, Meiling Zhang, Yi Wang, Guohua Liang, Qian Qian, Song Ge, Kang Chong

{"title":"COLD6-OSM1 module senses chilling for cold tolerance via 2′,3′-cAMP signaling in rice","authors":"Wei Luo, Yunyuan Xu, Jie Cao, Xiaoyu Guo, Jingdan Han, Yuanyuan Zhang, Yuda Niu, Meiling Zhang, Yi Wang, Guohua Liang, Qian Qian, Song Ge, Kang Chong","doi":"10.1016/j.molcel.2024.09.031","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.031","url":null,"abstract":"While it is known that temperature sensors trigger calcium (Ca2+) signaling to confer cold tolerance in cells, less is known about sensors that couple with other secondary messengers. Here, we identify a cold sensor complex of CHILLING-TOLERANCE DIVERGENCE 6 (COLD6) and osmotin-like 1 (OSM1), which triggers 2′,3′-cyclic adenosine monophosphate (2′,3′-cAMP) production to enhance cold tolerance in rice. COLD6, which is encoded by a major quantitative trait locus (QTL) gene, interacts with the rice G protein α subunit (RGA1) at the plasma membrane under normal conditions. Upon exposure to chilling, cold-induced OSM1 binds to COLD6, kicking out RGA1 from interaction. This triggers an elevation of 2′,3′-cAMP levels for enhancing chilling tolerance. Genetic data show that COLD6 negatively regulates cold tolerance and functionally depends on OSM1 in chilling stress. COLD6 alleles were selected during rice domestication. Knockout and natural variation of COLD6 in hybrid rice enhanced chilling tolerance, hinting design potential for breeding. This highlighted a module triggering 2′,3′-cAMP to improve chilling tolerance in crops.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541581","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}

引用次数: 0

Tumor-suppressive activities for pogo transposable element derived with KRAB domain via ribosome biogenesis restriction 带有 KRAB 结构域的 pogo 转座元件通过核糖体生物生成限制产生抑癌活性

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-30 DOI: 10.1016/j.molcel.2024.09.025

Zhenbo Tu, Mahmoud A. Bassal, George W. Bell, Yanzhou Zhang, Yi Hu, Liza M. Quintana, Deeptha Gokul, Daniel G. Tenen, Antoine E. Karnoub

{"title":"Tumor-suppressive activities for pogo transposable element derived with KRAB domain via ribosome biogenesis restriction","authors":"Zhenbo Tu, Mahmoud A. Bassal, George W. Bell, Yanzhou Zhang, Yi Hu, Liza M. Quintana, Deeptha Gokul, Daniel G. Tenen, Antoine E. Karnoub","doi":"10.1016/j.molcel.2024.09.025","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.025","url":null,"abstract":"Transposable elements (TEs) are indispensable for human development, with critical functions in pluripotency and embryogenesis. TE sequences also contribute to human pathologies, especially cancer, with documented activities as cis/trans transcriptional regulators, as sources of non-coding RNAs, and as mutagens that disrupt tumor suppressors. Despite this knowledge, little is known regarding the involvement of TE-derived genes (TEGs) in tumor pathogenesis. Here, systematic analyses of TEG expression across human cancer reveal a prominent role for pogo TE derived with KRAB domain (POGK). We show that POGK acts as a tumor suppressor in triple-negative breast cancer (TNBC) cells and that it couples with the co-repressor TRIM28 to directly block the transcription of ribosomal genes RPS16 and RPS29, in turn causing widespread inhibition of ribosomal biogenesis. We report that POGK undergoes deactivation by isoform switching in clinical TNBC, altogether revealing its exapted activities in tumor growth control.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541578","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}

引用次数: 0

Excessive MYC-topoisome activity triggers acute DNA damage, MYC degradation, and replacement by a p53-topoisome 过度的 MYC-拓扑结构活性会引发急性 DNA 损伤、MYC 降解并被 p53-拓扑结构所取代

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-30 DOI: 10.1016/j.molcel.2024.10.006

Subhendu K. Das, Sharmistha Karmakar, Harish Venkatachalapathy, Rajiv Kumar Jha, Eric Batchelor, David Levens

引用次数: 0

Transient promoter interactions modulate developmental gene activation 瞬时启动子相互作用调节发育基因的激活

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-29 DOI: 10.1016/j.molcel.2024.10.005

Sylvia Mahara, Sonja Prüssing, Valeriia Smialkovska, Samuel Krall, Susannah Holliman, Belinda Blum, Victoria Dachtler, Helena Borgers, Etienne Sollier, Christoph Plass, Angelika Feldmann

{"title":"Transient promoter interactions modulate developmental gene activation","authors":"Sylvia Mahara, Sonja Prüssing, Valeriia Smialkovska, Samuel Krall, Susannah Holliman, Belinda Blum, Victoria Dachtler, Helena Borgers, Etienne Sollier, Christoph Plass, Angelika Feldmann","doi":"10.1016/j.molcel.2024.10.005","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.005","url":null,"abstract":"Transcriptional induction coincides with the formation of various chromatin topologies. Strong evidence supports that gene activation is accompanied by a general increase in promoter-enhancer interactions. However, it remains unclear how these topological changes are coordinated across time and space during transcriptional activation. Here, we combine chromatin conformation capture with transcription and chromatin profiling during an embryonic stem cell (ESC) differentiation time course to determine how 3D genome restructuring is related to transcriptional transitions. This approach allows us to identify distinct topological alterations that are associated with the magnitude of transcriptional induction. We detect transiently formed interactions and demonstrate by genetic deletions that associated distal regulatory elements (DREs), as well as appropriate formation and disruption of these interactions, can contribute to the transcriptional induction of linked genes. Together, our study links topological dynamics to the magnitude of transcriptional induction and detects an uncharacterized type of transcriptionally important DREs.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536559","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}

引用次数: 0

Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway 棕榈酰化许可 TNF 通路中的 RIPK1 激酶活性和细胞毒性

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-28 DOI: 10.1016/j.molcel.2024.10.002

Na Zhang, Jianping Liu, Rui Guo, Lingjie Yan, Yuanxin Yang, Chen Shi, Mengmeng Zhang, Bing Shan, Wanjin Li, Jinyang Gu, Daichao Xu

{"title":"Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway","authors":"Na Zhang, Jianping Liu, Rui Guo, Lingjie Yan, Yuanxin Yang, Chen Shi, Mengmeng Zhang, Bing Shan, Wanjin Li, Jinyang Gu, Daichao Xu","doi":"10.1016/j.molcel.2024.10.002","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.002","url":null,"abstract":"Tumor necrosis factor (TNF)-induced receptor-interacting serine/threonine protein kinase 1 (RIPK1)-mediated cell death, including apoptosis and necroptosis, is increasingly recognized as a major driver of inflammatory diseases. Cell death checkpoints normally suppress RIPK1 kinase to safeguard the organism from its detrimental consequences. However, the mechanisms licensing RIPK1 kinase activity when a protective checkpoint is disabled remain unclear. Here, we identified S-palmitoylation as a licensing modification for RIPK1 kinase. TNF induces RIPK1 palmitoylation, mediated by DHHC5 and dependent on K63-linked ubiquitination of RIPK1, which enhances RIPK1 kinase activity by promoting the homo-interaction of its kinase domain and promotes cell death upon cell death checkpoint blockade. Furthermore, DHHC5 is amplified by fatty acid in the livers of mice with metabolic dysfunction-associated steatohepatitis, contributing to increased RIPK1 cytotoxicity observed in this condition. Our findings reveal that ubiquitination-dependent palmitoylation licenses RIPK1 kinase activity to induce downstream cell death signaling and suggest RIPK1 palmitoylation as a feasible target for inflammatory diseases.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519561","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}

引用次数: 0