Molecular Cell最新文献_第3页

UbiREAD deciphers proteasomal degradation code of homotypic and branched K48 and K63 ubiquitin chains

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-24 DOI: 10.1016/j.molcel.2025.02.021

Leo Kiss, Leo C. James, Brenda A. Schulman

{"title":"UbiREAD deciphers proteasomal degradation code of homotypic and branched K48 and K63 ubiquitin chains","authors":"Leo Kiss, Leo C. James, Brenda A. Schulman","doi":"10.1016/j.molcel.2025.02.021","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.02.021","url":null,"abstract":"Ubiquitin chains define the fates of their modified proteins, often mediating proteasomal degradation in eukaryotes. Yet heterogeneity of intracellular ubiquitination has precluded systematically comparing the degradation capacities of different ubiquitin chains. We developed ubiquitinated reporter evaluation after intracellular delivery (UbiREAD), a technology that monitors cellular degradation and deubiquitination at high temporal resolution after bespoke ubiquitinated proteins are delivered into human cells. Comparing the degradation of a model substrate modified with various K48, K63, or K48/K63-branched ubiquitin chains revealed fundamental differences in their intracellular degradation capacities. K48 chains with three or more ubiquitins triggered degradation within minutes. K63-ubiquitinated substrate was rapidly deubiquitinated rather than degraded. Surprisingly, in K48/K63-branched chains, substrate-anchored chain identity determined the degradation and deubiquitination behavior, establishing that branched chains are not the sum of their parts. UbiREAD reveals a degradation code for ubiquitin chains varying by linkage, length, and topology and a functional hierarchy within branched ubiquitin chains.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"61 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677851","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

PI3Kβ functions as a protein kinase to promote cellular protein O-GlcNAcylation and acetyl-CoA production for tumor growth

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-24 DOI: 10.1016/j.molcel.2025.02.024

Xuxiao He, Deyu Chen, Guijun Liu, Qingang Wu, Hong Zhao, Dong Guo, Xiaoming Jiang, Min Li, Ying Meng, Yucheng Yin, Xianglai Ye, Shudi Luo, Yan Xia, Tony Hunter, Zhimin Lu

{"title":"PI3Kβ functions as a protein kinase to promote cellular protein O-GlcNAcylation and acetyl-CoA production for tumor growth","authors":"Xuxiao He, Deyu Chen, Guijun Liu, Qingang Wu, Hong Zhao, Dong Guo, Xiaoming Jiang, Min Li, Ying Meng, Yucheng Yin, Xianglai Ye, Shudi Luo, Yan Xia, Tony Hunter, Zhimin Lu","doi":"10.1016/j.molcel.2025.02.024","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.02.024","url":null,"abstract":"Phosphatidylinositol 3-kinase (PI3K) phosphorylates PI(4,5)P2 to produce PI(3,4,5)P3, thereby activating AKT and other effector proteins. However, whether PI3K has non-PI(3,4,5)P3-related functions critical for tumor development remains unclear. Here, we demonstrate that high glucose induces PI3Kβ binding to O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) in glioblastoma cells, dependent on hexokinase 1 (HK1)-mediated OGT Y889 phosphorylation and subsequent p85α recruitment. Importantly, PI3Kβ functions as a protein kinase, phosphorylating OGT at T985 and enhancing OGT activity and total cellular protein O-GlcNAcylation. Activated OGT O-GlcNAcylates ATP-citrate synthase (ACLY) at T639 and S667, leading to ACLY activation-dependent acetyl-coenzyme A (CoA) production to increase fatty acid levels and histone H3 acetylation for gene transcription. Intervention in PI3Kβ-mediated OGT phosphorylation and ACLY O-GlcNAcylation inhibits glioblastoma cell proliferation and tumor growth in xenografts. These findings underscore the critical role of PI3Kβ in governing protein O-GlcNAcylation, fatty acid metabolism, and chromatin modification through its protein kinase activity and provide instrumental insight into the roles of PI3K in tumor progression.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"71 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677853","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

Proteome-wide discovery of phage anti-defense proteins by Alphafold2

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-20 DOI: 10.1016/j.molcel.2025.02.020

Zhifu Han, Yu Cao, Jijie Chai

引用次数: 0

A cut above: Bacterial deubiquitinases with ubiquitin clippase activity

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-20 DOI: 10.1016/j.molcel.2025.02.023

Mark Hochstrasser

引用次数: 0

Lost in translation: SLFN11 induces p53-independent apoptosis

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-20 DOI: 10.1016/j.molcel.2025.02.029

Andrew E.H. Elia, Snehanshu Chowdhury, William R. DeNight

引用次数: 0

β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-20 DOI: 10.1016/j.molcel.2025.02.022

Min Tang, Yingfeng Tu, Yanqiu Gong, Qin Yang, Jinrui Wang, Zhenzhen Zhang, Junhong Qin, Shenghui Niu, Jiamin Yi, Zehua Shang, Hongyu Chen, Yingying Tang, Qian Huang, Yanmei Liu, Daniel D. Billadeau, Xingguo Liu, Lunzhi Dai, Da Jia

{"title":"β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions","authors":"Min Tang, Yingfeng Tu, Yanqiu Gong, Qin Yang, Jinrui Wang, Zhenzhen Zhang, Junhong Qin, Shenghui Niu, Jiamin Yi, Zehua Shang, Hongyu Chen, Yingying Tang, Qian Huang, Yanmei Liu, Daniel D. Billadeau, Xingguo Liu, Lunzhi Dai, Da Jia","doi":"10.1016/j.molcel.2025.02.022","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.02.022","url":null,"abstract":"Mitochondrial dynamics and metabolites reciprocally influence each other. Mitochondrial-derived vesicles (MDVs) transport damaged mitochondrial components to lysosomes or the extracellular space. While many metabolites are known to modulate mitochondrial dynamics, it is largely unclear whether they are involved in MDV generation. Here, we discovered that the major component of ketone body, β-hydroxybutyrate (BHB), improved mitochondrial functions by facilitating the biogenesis of MDVs. Mechanistically, BHB drove specific lysine β-hydroxybutyrylation (Kbhb) of sorting nexin-9 (SNX9), a key regulator of MDV biogenesis. Kbhb increased SNX9 interaction with inner mitochondrial membrane (IMM)/matrix proteins and promoted the formation of IMM/matrix MDVs. SNX9 Kbhb was not only critical for maintaining mitochondrial homeostasis in cells but also protected mice from alcohol-induced liver injury. Altogether, our research uncovers the fact that metabolites influence the formation of MDVs by directly engaging in post-translational modifications of key protein machineries and establishes a framework for understanding how metabolites regulate mitochondrial functions.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"20 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660406","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

Unlocking protein networks with Predictomes: The SPOC advantage

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-20 DOI: 10.1016/j.molcel.2025.02.010

Arne Elofsson

引用次数: 0

Autonomous shaping of the piRNA sequence repertoire by competition between adjacent ping-pong amplification sites

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-20 DOI: 10.1016/j.molcel.2025.02.015

Jie Yu, Fumiko Kawasaki, Natsuko Izumi, Takashi Kiuchi, Susumu Katsuma, Yukihide Tomari, Keisuke Shoji

{"title":"Autonomous shaping of the piRNA sequence repertoire by competition between adjacent ping-pong amplification sites","authors":"Jie Yu, Fumiko Kawasaki, Natsuko Izumi, Takashi Kiuchi, Susumu Katsuma, Yukihide Tomari, Keisuke Shoji","doi":"10.1016/j.molcel.2025.02.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.02.015","url":null,"abstract":"PIWI-interacting RNAs (piRNAs) are crucial for silencing transposable elements (TEs). In many species, piRNAs are generated via a complex process known as the ping-pong pathway, coupling TE cleavage with piRNA amplification. However, the biological significance of this complexity remains unclear. Here, we systematically compared piRNA profiles in two related silkworm cell lines and found significant changes in their sequence repertoire. Importantly, the changeability of this repertoire negatively correlated with the piRNA biogenesis efficiency, a trend also observed in Drosophila stocks and single silkworm eggs. This can be explained by competition between adjacent ping-pong sites, supported by our mathematical modeling. Moreover, this competition can rationalize how piRNAs autonomously avoid deleterious mismatches to target TEs in silkworms, flies, and mice. These findings unveil the intrinsic plasticity and adaptability of the piRNA system to combat diverse TE sequences and highlight the universal power of competition and self-amplification to drive autonomous optimization.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"61 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660405","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

Isogenic comparison of Airn and Xist reveals core principles of Polycomb recruitment by lncRNAs

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-20 DOI: 10.1016/j.molcel.2025.02.014

Jackson B. Trotman, Elizabeth W. Abrash, McKenzie M. Murvin, Aki K. Braceros, Shuang Li, Samuel P. Boyson, Ryan T. Salcido, Rachel E. Cherney, Steven R. Bischoff, Kyle Kaufmann, Quinn E. Eberhard, Zhiyue Zhang, Dale O. Cowley, J. Mauro Calabrese

{"title":"Isogenic comparison of Airn and Xist reveals core principles of Polycomb recruitment by lncRNAs","authors":"Jackson B. Trotman, Elizabeth W. Abrash, McKenzie M. Murvin, Aki K. Braceros, Shuang Li, Samuel P. Boyson, Ryan T. Salcido, Rachel E. Cherney, Steven R. Bischoff, Kyle Kaufmann, Quinn E. Eberhard, Zhiyue Zhang, Dale O. Cowley, J. Mauro Calabrese","doi":"10.1016/j.molcel.2025.02.014","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.02.014","url":null,"abstract":"The mechanisms and biological roles of Polycomb repressive complex (PRC) recruitment by long noncoding RNAs (lncRNAs) remain unclear. To gain insight, we expressed two lncRNAs that recruit PRCs to multi-megabase domains, Airn and Xist, from an ectopic locus in mouse stem cells and compared effects. Unexpectedly, ectopic Airn recruited PRC1 and PRC2 to chromatin with a potency resembling Xist yet did not repress genes. Compared with PRC2, PRC1 was more proximal to Airn and Xist, where its enrichment over C-rich elements required the RNA-binding protein HNRNPK. Fusing Airn to Repeat A, the domain required for gene silencing by Xist, enabled gene silencing and altered local patterns but not relative levels of PRC-directed modifications. Our data suggest that, endogenously, Airn recruits PRCs to maintain rather than initiate gene silencing, that PRC recruitment occurs independently of Repeat A, and that protein-bridged interactions, not direct RNA contacts, underlie PRC recruitment by Airn, Xist, and other lncRNAs.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"70 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660409","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

Mind the gap: Intergenic regions in bacteria encode numerous small proteins

IF 16 1区生物学

Molecular Cell Pub Date : 2025-03-20 DOI: 10.1016/j.molcel.2025.02.018

Jordan D. Lin, Ami S. Bhatt

引用次数: 0