Molecular Cell最新文献

Structural basis of BAK sequestration by MCL-1 in apoptosis

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-04 DOI: 10.1016/j.molcel.2025.03.013

Shagun Srivastava, Giridhar Sekar, Adedolapo Ojoawo, Anup Aggarwal, Elisabeth Ferreira, Emiko Uchikawa, Meek Yang, Christy R. Grace, Raja Dey, Yi-Lun Lin, Cristina D. Guibao, Seetharaman Jayaraman, Somnath Mukherjee, Anthony A. Kossiakoff, Bin Dong, Alexander Myasnikov, Tudor Moldoveanu

{"title":"Structural basis of BAK sequestration by MCL-1 in apoptosis","authors":"Shagun Srivastava, Giridhar Sekar, Adedolapo Ojoawo, Anup Aggarwal, Elisabeth Ferreira, Emiko Uchikawa, Meek Yang, Christy R. Grace, Raja Dey, Yi-Lun Lin, Cristina D. Guibao, Seetharaman Jayaraman, Somnath Mukherjee, Anthony A. Kossiakoff, Bin Dong, Alexander Myasnikov, Tudor Moldoveanu","doi":"10.1016/j.molcel.2025.03.013","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.013","url":null,"abstract":"Apoptosis controls cell fate, ensuring tissue homeostasis and promoting disease when dysregulated. The rate-limiting step in apoptosis is mitochondrial poration by the effector B cell lymphoma 2 (BCL-2) family proteins BAK and BAX, which are activated by initiator BCL-2 homology 3 (BH3)-only proteins (e.g., BIM) and inhibited by guardian BCL-2 family proteins (e.g., MCL-1). We integrated structural, biochemical, and pharmacological approaches to characterize the human prosurvival MCL-1:BAK complex assembled from their BCL-2 globular core domains. We reveal a canonical interaction with BAK BH3 bound to the hydrophobic groove of MCL-1 and disordered and highly dynamic BAK regions outside the complex interface. We predict similar conformations of activated effectors in complex with other guardians or effectors. The MCL-1:BAK complex is a major cancer drug target. We show that MCL-1 inhibitors are inefficient in neutralizing the MCL-1:BAK complex, requiring high doses to initiate apoptosis. Our study underscores the need to design superior clinical candidate MCL-1 inhibitors.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"34 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775922","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 nuclear RNA degradation code is recognized by PAXT for eukaryotic transcriptome surveillance

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-04 DOI: 10.1016/j.molcel.2025.03.010

Lindsey V. Soles, Liang Liu, Xudong Zou, Yoseop Yoon, Shuangyu Li, Lusong Tian, Marielle Valdez, Angela M Yu, Hong Yin, Wei Li, Fangyuan Ding, Georg Seelig, Lei Li, Yongsheng Shi

{"title":"A nuclear RNA degradation code is recognized by PAXT for eukaryotic transcriptome surveillance","authors":"Lindsey V. Soles, Liang Liu, Xudong Zou, Yoseop Yoon, Shuangyu Li, Lusong Tian, Marielle Valdez, Angela M Yu, Hong Yin, Wei Li, Fangyuan Ding, Georg Seelig, Lei Li, Yongsheng Shi","doi":"10.1016/j.molcel.2025.03.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.010","url":null,"abstract":"The RNA exosome plays critical roles in eukaryotic RNA degradation, but how it specifically recognizes its targets remains unclear. The poly(A) tail exosome targeting (PAXT) connection is a nuclear adaptor that recruits the exosome to polyadenylated RNAs, especially transcripts polyadenylated at intronic poly(A) sites. Here, we show that PAXT-mediated RNA degradation is induced by the combination of a 5′ splice site (ss) and a poly(A) junction (PAJ) but not by either sequence alone. These sequences are bound by U1 small nuclear ribonucleoprotein particle (snRNP) and cleavage/polyadenylation factors, which, in turn, cooperatively recruit PAXT. As the 5′ ss-PAJ combination is typically absent on correctly processed RNAs, it functions as a “nuclear RNA degradation code” (NRDC). Importantly, disease-associated single nucleotide polymorphisms that create novel 5′ ss in 3′ untranslated regions can induce aberrant mRNA degradation via the NRDC mechanism. Together, our study identified the first NRDC, revealed its recognition mechanism, and characterized its role in human diseases.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"23 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776162","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

Acetylation of METTL3: A negative regulator of m6A deposition on chromatin-associated regulatory RNAs

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-03 DOI: 10.1016/j.molcel.2025.03.002

Yutao Zhao, Chuan He

引用次数: 0

Deconstructing destruction: A rapid route to proteasomal fate

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-03 DOI: 10.1016/j.molcel.2025.03.011

Elena Maspero, Simona Polo

引用次数: 0

STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-03 DOI: 10.1016/j.molcel.2025.03.008

Zhen Tang, Cong Xing, Antonina Araszkiewicz, Kun Yang, Wanwan Huai, Devon Jeltema, Nicole Dobbs, Yihe Zhang, Lu O. Sun, Nan Yan

{"title":"STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders","authors":"Zhen Tang, Cong Xing, Antonina Araszkiewicz, Kun Yang, Wanwan Huai, Devon Jeltema, Nicole Dobbs, Yihe Zhang, Lu O. Sun, Nan Yan","doi":"10.1016/j.molcel.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.008","url":null,"abstract":"Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with diseases like lysosomal storage disorders (LSDs). How lysosomal defects are detected and lysosomal function restored remain incompletely understood. Here, we show that STING mediates a neuroinflammatory gene signature in three distinct LSD mouse models, Galctwi/twi, Ppt1−/−, and Cln7−/−. Transcriptomic analysis of Galctwi/twi mouse brain tissue revealed that STING also mediates the expression of lysosomal genes that are regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-sequencing (snRNA-seq) analysis show that STING regulates lysosomal gene expression in microglia. Mechanistically, we show that STING activation leads to TFEB dephosphorylation, nuclear translocation, and expression of lysosomal genes. This process requires STING’s proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Furthermore, we show that the STING-TFEB axis facilitates lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control mechanism that responds to lysosomal dysfunction.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"33 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766803","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

An ultraconserved snoRNA-like element in long noncoding RNA CRNDE promotes ribosome biogenesis and cell proliferation

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-03 DOI: 10.1016/j.molcel.2025.03.006

Jong-Sun Lee, Tu Dan, He Zhang, Yujing Cheng, Frederick Rehfeld, James Brugarolas, Joshua T. Mendell

{"title":"An ultraconserved snoRNA-like element in long noncoding RNA CRNDE promotes ribosome biogenesis and cell proliferation","authors":"Jong-Sun Lee, Tu Dan, He Zhang, Yujing Cheng, Frederick Rehfeld, James Brugarolas, Joshua T. Mendell","doi":"10.1016/j.molcel.2025.03.006","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.03.006","url":null,"abstract":"Cancer cells frequently upregulate ribosome production to support tumorigenesis. While small nucleolar RNAs (snoRNAs) are critical for ribosome biogenesis, the roles of other classes of noncoding RNAs in this process remain largely unknown. Here, we performed CRISPR interference (CRISPRi) screens to identify essential long noncoding RNAs (lncRNAs) in renal cell carcinoma (RCC) cells. This revealed that an alternatively spliced isoform of lncRNA colorectal neoplasia differentially expressed (CRNDE) containing an ultraconserved element (UCE), referred to as CRNDEUCE, is required for RCC cell proliferation. CRNDEUCE localizes to the nucleolus and promotes 60S ribosomal subunit biogenesis. The UCE of CRNDE functions as an unprocessed C/D box snoRNA that directly interacts with ribosomal RNA precursors. This facilitates delivery of eukaryotic initiation factor 6 (eIF6), a key 60S biogenesis factor, which binds to CRNDEUCE through a sequence element adjacent to the UCE. These findings highlight the functional versatility of snoRNA sequences and expand the known mechanisms through which noncoding RNAs orchestrate ribosome biogenesis.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"33 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766841","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

Hypoxia-induced phase separation of ZHX2 alters chromatin looping to drive cancer metastasis

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-03 DOI: 10.1016/j.molcel.2025.03.009

Chuan Gao, Ang Gao, Yulong Jiang, Ronghui Gao, Yan Guo, Zirou Peng, Weiwei Jiang, Mengyao Zhang, Zirui Zhou, Chaojun Yan, Wentong Fang, Hankun Hu, Guangya Zhu, Jing Zhang

引用次数: 0

Hijacking the powerhouse: Mitochondrial transfer and mitophagy as emerging mechanisms of immune evasion

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-03 DOI: 10.1016/j.molcel.2025.02.026

Maria T. Diaz-Meco, Juan F. Linares, Jorge Moscat

引用次数: 0

Metabolite tunes MDV pathway to maintain mitochondrial fitness

IF 16 1区生物学

Molecular Cell Pub Date : 2025-04-03 DOI: 10.1016/j.molcel.2025.02.027

Shiori Sekine, Yusuke Sekine

引用次数: 0

Tackling a textbook example of multistep enzyme catalysis with deep learning-driven design