Molecular Cell最新文献_第9页

The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism

IF 16 1区生物学

Molecular Cell Pub Date : 2025-01-30 DOI: 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

{"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}

引用次数: 0

Convergence of orphan quality control pathways at a ubiquitin chain-elongating ligase

IF 16 1区生物学

Molecular Cell Pub Date : 2025-01-28 DOI: 10.1016/j.molcel.2025.01.002

Sara Carrillo Roas, Yuichi Yagita, Paul Murphy, Robert Kurzbauer, Tim Clausen, Eszter Zavodszky, Ramanujan S. Hegde

{"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}

引用次数: 0

OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth

IF 16 1区生物学

Molecular Cell Pub Date : 2025-01-24 DOI: 10.1016/j.molcel.2024.12.025

Dong Guo, Qiujing Yu, Yingying Tong, Xu Qian, Ying Meng, Fei Ye, Xiaoming Jiang, Lihui Wu, Qingqing Yang, Suyao Li, Min Li, Qingang Wu, Liwei Xiao, Xuxiao He, Rongxuan Zhu, Guijun Liu, Dou Nie, Shudi Luo, Leina Ma, Ren-an Jin, Zhimin Lu

{"title":"OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth","authors":"Dong Guo, Qiujing Yu, Yingying Tong, Xu Qian, Ying Meng, Fei Ye, Xiaoming Jiang, Lihui Wu, Qingqing Yang, Suyao Li, Min Li, Qingang Wu, Liwei Xiao, Xuxiao He, Rongxuan Zhu, Guijun Liu, Dou Nie, Shudi Luo, Leina Ma, Ren-an Jin, Zhimin Lu","doi":"10.1016/j.molcel.2024.12.025","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.025","url":null,"abstract":"Ketone bodies generated in hepatocytes in the adult liver are used for nonhepatic tissues as an energy source. However, ketolysis is reactivated in hepatocellular carcinoma (HCC) cells with largely unelucidated mechanisms. Here, we demonstrate that 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting enzyme in ketolysis, interacts with SUCLA2 upon IGF1 stimulation in HCC cells. This interaction results from ERK2-mediated SUCLA2 S124 phosphorylation and subsequent PIN1-mediated <em>cis-trans</em> isomerization of SUCLA2. OXCT1-associated SUCLA2 generates succinyl-CoA, which not only serves as a substrate for OXCT1 but also directly succinylates OXCT1 at K421 and activates OXCT1. SUCLA2-regulated OXCT1 activation substantially enhances ketolysis, HCC cell proliferation, and tumor growth in mice. Notably, treatment with acetohydroxamic acid, an OXCT1 inhibitor used clinically for urinary infection, inhibits liver tumor growth in mice and significantly enhances lenvatinib therapy. Our findings highlight the role of SUCLA2-coupled regulation of OXCT1 succinylation in ketolysis and unveil an unprecedented strategy for treating HCC by interrupting ketolysis.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"110 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026715","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

Cytoplasmic mRNA decay controlling inflammatory gene expression is determined by pre-mRNA fate decision

IF 16 1区生物学

Molecular Cell Pub Date : 2025-01-24 DOI: 10.1016/j.molcel.2025.01.001

Annika Bestehorn, Julius von Wirén, Christina Zeiler, Jeanne Fesselet, Sebastian Didusch, Maurizio Forte, Kevin Doppelmayer, Martina Borroni, Anita Le Heron, Sara Scinicariello, WeiQiang Chen, Manuela Baccarini, Vera Pfanzagl, Gijs A. Versteeg, Markus Hartl, Pavel Kovarik

{"title":"Cytoplasmic mRNA decay controlling inflammatory gene expression is determined by pre-mRNA fate decision","authors":"Annika Bestehorn, Julius von Wirén, Christina Zeiler, Jeanne Fesselet, Sebastian Didusch, Maurizio Forte, Kevin Doppelmayer, Martina Borroni, Anita Le Heron, Sara Scinicariello, WeiQiang Chen, Manuela Baccarini, Vera Pfanzagl, Gijs A. Versteeg, Markus Hartl, Pavel Kovarik","doi":"10.1016/j.molcel.2025.01.001","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.01.001","url":null,"abstract":"The fidelity of immune responses depends on timely controlled and selective mRNA degradation that is largely driven by RNA-binding proteins (RBPs). It remains unclear whether stochastic or directed processes govern the selection of an individual mRNA molecule for degradation. Using human and mouse cells, we show that tristetraprolin (TTP, also known as ZFP36), an essential anti-inflammatory RBP, destabilizes target mRNAs via a hierarchical molecular assembly. The assembly formation strictly relies on the interaction of TTP with RNA. The TTP homolog ZFP36L1 exhibits similar requirements, indicating a broader relevance of this regulatory program. Unexpectedly, the assembly of the cytoplasmic mRNA-destabilization complex is licensed in the nucleus by TTP binding to pre-mRNA, which we identify as the principal TTP target rather than mRNA. Hence, the fate of an inflammation-induced mRNA is decided concomitantly with its synthesis. This mechanism prevents the translation of excessive and potentially harmful inflammation mediators, irrespective of transcription.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"34 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026714","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

Microexon in action: How tiny fragments in a protein tune function, drive disease 微外显子的作用：蛋白质中的微小片段如何调节功能，驱动疾病

IF 16 1区生物学

Molecular Cell Pub Date : 2025-01-16 DOI: 10.1016/j.molcel.2024.12.022

Jie-rong Huang

引用次数: 0

Molecular determinants of condensate composition 冷凝物组成的分子决定因素

IF 16 1区生物学

Molecular Cell Pub Date : 2025-01-16 DOI: 10.1016/j.molcel.2024.12.021

Alex S. Holehouse, Simon Alberti

引用次数: 0

Nucleic acid recognition during prokaryotic immunity 原核免疫过程中的核酸识别