Molecular Cell最新文献_第10页

OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB OXCT1 作为琥珀酰基转移酶，通过琥珀酰化 LACTB 促进肝细胞癌的发生

IF 16 1区生物学

Molecular Cell Pub Date : 2024-01-03 DOI: 10.1016/j.molcel.2023.11.042

Wenhao Ma, Yuchen Sun, Ronghui Yan, Pinggen Zhang, Shengqi Shen, Hui Lu, Zilong Zhou, Zetan Jiang, Ling Ye, Qiankun Mao, Nanchi Xiong, Weidong Jia, Linchong Sun, Ping Gao, Huafeng Zhang

{"title":"OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB","authors":"Wenhao Ma, Yuchen Sun, Ronghui Yan, Pinggen Zhang, Shengqi Shen, Hui Lu, Zilong Zhou, Zetan Jiang, Ling Ye, Qiankun Mao, Nanchi Xiong, Weidong Jia, Linchong Sun, Ping Gao, Huafeng Zhang","doi":"10.1016/j.molcel.2023.11.042","DOIUrl":"https://doi.org/10.1016/j.molcel.2023.11.042","url":null,"abstract":"Metabolic reprogramming is an important feature of cancers that has been closely linked to post-translational protein modification (PTM). Lysine succinylation is a recently identified PTM involved in regulating protein functions, whereas its regulatory mechanism and possible roles in tumor progression remain unclear. Here, we show that OXCT1, an enzyme catalyzing ketone body oxidation, functions as a lysine succinyltransferase to contribute to tumor progression. Mechanistically, we find that OXCT1 functions as a succinyltransferase, with residue G424 essential for this activity. We also identified serine beta-lactamase-like protein (LACTB) as a main target of OXCT1-mediated succinylation. Extensive succinylation of LACTB K284 inhibits its proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, ultimately leading to hepatocellular carcinoma (HCC) progression. In summary, this study establishes lysine succinyltransferase function of OXCT1 and highlights a link between HCC prognosis and LACTB K284 succinylation, suggesting a potentially valuable biomarker and therapeutic target for further development.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"18 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139091917","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

Recruitment of trimeric eIF2 by phosphatase non-catalytic subunit PPP1R15B 磷酸酶非催化亚基 PPP1R15B 对三聚体 eIF2 的招募

IF 16 1区生物学

Molecular Cell Pub Date : 2023-12-29 DOI: 10.1016/j.molcel.2023.12.011

Agnieszka Fatalska, George Hodgson, Stefan M.V. Freund, Sarah L. Maslen, Tomos Morgan, Sigurdur R. Thorkelsson, Marjon van Slegtenhorst, Sonja Lorenz, Antonina Andreeva, Laura Donker Kaat, Anne Bertolotti

{"title":"Recruitment of trimeric eIF2 by phosphatase non-catalytic subunit PPP1R15B","authors":"Agnieszka Fatalska, George Hodgson, Stefan M.V. Freund, Sarah L. Maslen, Tomos Morgan, Sigurdur R. Thorkelsson, Marjon van Slegtenhorst, Sonja Lorenz, Antonina Andreeva, Laura Donker Kaat, Anne Bertolotti","doi":"10.1016/j.molcel.2023.12.011","DOIUrl":"https://doi.org/10.1016/j.molcel.2023.12.011","url":null,"abstract":"Regulated protein phosphorylation controls most cellular processes. The protein phosphatase PP1 is the catalytic subunit of many holoenzymes that dephosphorylate serine/threonine residues. How these enzymes recruit their substrates is largely unknown. Here, we integrated diverse approaches to elucidate how the PP1 non-catalytic subunit PPP1R15B (R15B) captures its full trimeric eIF2 substrate. We found that the substrate-recruitment module of R15B is largely disordered with three short helical elements, H1, H2, and H3. H1 and H2 form a clamp that grasps the substrate in a region remote from the phosphorylated residue. A homozygous N423D variant, adjacent to H1, reducing substrate binding and dephosphorylation was discovered in a rare syndrome with microcephaly, developmental delay, and intellectual disability. These findings explain how R15B captures its 125 kDa substrate by binding the far end of the complex relative to the phosphosite to present it for dephosphorylation by PP1, a paradigm of broad relevance.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"2 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139060734","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

p300 is an obligate integrator of combinatorial transcription factor inputs p300 是组合转录因子输入的强制性整合因子

IF 16 1区生物学

Molecular Cell Pub Date : 2023-12-29 DOI: 10.1016/j.molcel.2023.12.004

John J. Ferrie, Jonathan P. Karr, Thomas G.W. Graham, Gina M. Dailey, Gloria Zhang, Robert Tjian, Xavier Darzacq

{"title":"p300 is an obligate integrator of combinatorial transcription factor inputs","authors":"John J. Ferrie, Jonathan P. Karr, Thomas G.W. Graham, Gina M. Dailey, Gloria Zhang, Robert Tjian, Xavier Darzacq","doi":"10.1016/j.molcel.2023.12.004","DOIUrl":"https://doi.org/10.1016/j.molcel.2023.12.004","url":null,"abstract":"Transcription coactivators are proteins or protein complexes that mediate transcription factor (TF) function. However, they lack DNA-binding capacity, prompting the question of how they engage target loci. Three non-exclusive hypotheses have been posited: coactivators are recruited by complexing with TFs, by binding histones through epigenetic reader domains, or by partitioning into condensates through their extensive intrinsically disordered regions. Using p300 as a prototypical coactivator, we systematically mutated its annotated domains and show by single-molecule tracking in live U2OS cells that coactivator-chromatin binding depends entirely on combinatorial binding of multiple TF-interaction domains. Furthermore, we demonstrate that acetyltransferase activity opposes p300-chromatin association and that the N-terminal TF-interaction domains regulate that activity. Single TF-interaction domains are insufficient for chromatin binding and regulation of catalytic activity, implying a principle that we speculate could broadly apply to eukaryotic gene regulation: a TF must act in coordination with other TFs to recruit coactivator activity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"81 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139060801","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

Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis AFG3L2 和铁对 SLC25A39 的双重调控控制着线粒体谷胱甘肽的稳态

IF 16 1区生物学

Molecular Cell Pub Date : 2023-12-28 DOI: 10.1016/j.molcel.2023.12.008

Xiaojian Shi, Marisa DeCiucis, Kariona A. Grabinska, Jean Kanyo, Adam Liu, Tukiet T. Lam, Hongying Shen

{"title":"Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis","authors":"Xiaojian Shi, Marisa DeCiucis, Kariona A. Grabinska, Jean Kanyo, Adam Liu, Tukiet T. Lam, Hongying Shen","doi":"10.1016/j.molcel.2023.12.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2023.12.008","url":null,"abstract":"Organelle transporters define metabolic compartmentalization, and how this metabolite transport process can be modulated is poorly explored. Here, we discovered that human SLC25A39, a mitochondrial transporter critical for mitochondrial glutathione uptake, is a short-lived protein under dual regulation at the protein level. Co-immunoprecipitation mass spectrometry and CRISPR knockout (KO) in mammalian cells identified that mitochondrial m-AAA protease AFG3L2 is responsible for degrading SLC25A39 through the matrix loop 1. SLC25A39 senses mitochondrial iron-sulfur cluster using four matrix cysteine residues and inhibits its degradation. SLC25A39 protein regulation is robust in developing and mature neurons. This dual transporter regulation, by protein quality control and metabolic sensing, allows modulating mitochondrial glutathione level in response to iron homeostasis, opening avenues for exploring regulation of metabolic compartmentalization. Neuronal SLC25A39 regulation connects mitochondrial protein quality control, glutathione, and iron homeostasis, which were previously unrelated biochemical features in neurodegeneration.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"4 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139059597","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

Chromatin gene-gene loops support the cross-regulation of genes with related function 染色质基因-基因环支持具有相关功能基因的交叉调节

IF 16 1区生物学

Molecular Cell Pub Date : 2023-12-28 DOI: 10.1016/j.molcel.2023.12.023

Tim Pollex, Raquel Marco-Ferreres, Lucia Ciglar, Yad Ghavi-Helm, Adam Rabinowitz, Rebecca Rodriguez Viales, Christoph Schaub, Aleksander Jankowski, Charles Girardot, Eileen E.M. Furlong

{"title":"Chromatin gene-gene loops support the cross-regulation of genes with related function","authors":"Tim Pollex, Raquel Marco-Ferreres, Lucia Ciglar, Yad Ghavi-Helm, Adam Rabinowitz, Rebecca Rodriguez Viales, Christoph Schaub, Aleksander Jankowski, Charles Girardot, Eileen E.M. Furlong","doi":"10.1016/j.molcel.2023.12.023","DOIUrl":"https://doi.org/10.1016/j.molcel.2023.12.023","url":null,"abstract":"Chromatin loops between gene pairs have been observed in diverse contexts in both flies and vertebrates. Combining high-resolution Capture-C, DNA fluorescence in situ hybridization, and genetic perturbations, we dissect the functional role of three loops between genes with related function during Drosophila embryogenesis. By mutating the loop anchor (but not the gene) or the gene (but not loop anchor), we disentangle loop formation and gene expression and show that the 3D proximity of paralogous gene loci supports their co-regulation. Breaking the loop leads to either an attenuation or enhancement of expression and perturbs their relative levels of expression and cross-regulation. Although many loops appear constitutive across embryogenesis, their function can change in different developmental contexts. Taken together, our results indicate that chromatin gene-gene loops act as architectural scaffolds that can be used in different ways in different contexts to fine-tune the coordinated expression of genes with related functions and sustain their cross-regulation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"23 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139060652","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

A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass 线粒体吞噬传感器 PPTC7 控制 BNIP3 和 NIX 降解以调节线粒体质量

IF 16 1区生物学

Molecular Cell Pub Date : 2023-12-26 DOI: 10.1016/j.molcel.2023.11.038

Yuqiu Sun, Yu Cao, Huayun Wan, Adalet Memetimin, Yang Cao, Lin Li, Chongyang Wu, Meng Wang, She Chen, Qi Li, Yan Ma, Mengqiu Dong, Hui Jiang

{"title":"A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass","authors":"Yuqiu Sun, Yu Cao, Huayun Wan, Adalet Memetimin, Yang Cao, Lin Li, Chongyang Wu, Meng Wang, She Chen, Qi Li, Yan Ma, Mengqiu Dong, Hui Jiang","doi":"10.1016/j.molcel.2023.11.038","DOIUrl":"https://doi.org/10.1016/j.molcel.2023.11.038","url":null,"abstract":"Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCFFBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCFFBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"9 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139041715","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

hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50 hRpn13 通过表观遗传因子 HDAC8、PADI4 和转录因子 NF-κB p50 塑造蛋白质组和转录组

IF 16 1区生物学

Molecular Cell Pub Date : 2023-12-26 DOI: 10.1016/j.molcel.2023.11.035

Vasty Osei-Amponsa, Monika Chandravanshi, Xiuxiu Lu, Valentin Magidson, Sudipto Das, Thorkell Andresson, Marzena Dyba, Venkata R. Sabbasani, Rolf E. Swenson, Caroline Fromont, Biraj Shrestha, Yongmei Zhao, Michelle E. Clapp, Raj Chari, Kylie J. Walters

{"title":"hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50","authors":"Vasty Osei-Amponsa, Monika Chandravanshi, Xiuxiu Lu, Valentin Magidson, Sudipto Das, Thorkell Andresson, Marzena Dyba, Venkata R. Sabbasani, Rolf E. Swenson, Caroline Fromont, Biraj Shrestha, Yongmei Zhao, Michelle E. Clapp, Raj Chari, Kylie J. Walters","doi":"10.1016/j.molcel.2023.11.035","DOIUrl":"https://doi.org/10.1016/j.molcel.2023.11.035","url":null,"abstract":"The anti-cancer target hRpn13 is a proteasome substrate receptor. However, hRpn13-targeting molecules do not impair its interaction with proteasomes or ubiquitin, suggesting other critical cellular activities. We find that hRpn13 depletion causes correlated proteomic and transcriptomic changes, with pronounced effects in myeloma cells for cytoskeletal and immune response proteins and bone-marrow-specific arginine deiminase PADI4. Moreover, a PROTAC against hRpn13 co-depletes PADI4, histone deacetylase HDAC8, and DNA methyltransferase MGMT. PADI4 binds and citrullinates hRpn13 and proteasomes, and proteasomes from PADI4-inhibited myeloma cells exhibit reduced peptidase activity. When off proteasomes, hRpn13 can bind HDAC8, and this interaction inhibits HDAC8 activity. Further linking hRpn13 to transcription, its loss reduces nuclear factor κB (NF-κB) transcription factor p50, which proteasomes generate by cleaving its precursor protein. NF-κB inhibition depletes hRpn13 interactors PADI4 and HDAC8. Altogether, we find that hRpn13 acts dually in protein degradation and expression and that proteasome constituency and, in turn, regulation varies by cell type.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"10 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139041694","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

Collisions of RNA polymerases behind the replication fork promote alternative RNA splicing in newly replicated chromatin 复制叉后 RNA 聚合酶的碰撞促进了新复制染色质中的替代 RNA 剪接

IF 16 1区生物学

Molecular Cell Pub Date : 2023-12-26 DOI: 10.1016/j.molcel.2023.11.036

Federica Bruno, Cristóbal Coronel-Guisado, Cristina González-Aguilera

引用次数: 0

The UFM1 system: Working principles, cellular functions, and pathophysiology UFM1 系统：工作原理、细胞功能和病理生理学

IF 16 1区生物学

Molecular Cell Pub Date : 2023-12-22 DOI: 10.1016/j.molcel.2023.11.034

Masaaki Komatsu, Toshifumi Inada, Nobuo N. Noda

引用次数: 0

Meet the authors: Yu Zhou, Ting Shan, and Feiyan Liu 与作者见面Yu Zhou、Ting Shan 和 Feiyan Liu

IF 16 1区生物学

Molecular Cell Pub Date : 2023-12-21 DOI: 10.1016/j.molcel.2023.11.039

Yu Zhou, Ting Shan, Feiyan Liu

引用次数: 0