Molecular CellPub Date : 2024-12-05DOI: 10.1016/j.molcel.2024.11.010
Maria Schwarz, Anna Patricia Kipp
{"title":"PRDX6 as an additional piece in the puzzle of selenoprotein synthesis","authors":"Maria Schwarz, Anna Patricia Kipp","doi":"10.1016/j.molcel.2024.11.010","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.010","url":null,"abstract":"In this issue of <em>Molecular Cell</em>, Ito et al.<span><span><sup>1</sup></span></span> and Chen et al.<span><span><sup>2</sup></span></span> identify peroxiredoxin 6 (PRDX6) as member of the selenoprotein (re)synthesis machinery, thereby linking PRDX6 to ferroptosis susceptibility of cancer cells.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"262 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776460","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}
Molecular CellPub Date : 2024-12-05DOI: 10.1016/j.molcel.2024.11.004
Rachael McMinimy, Andrew G. Manford, Christine L. Gee, Srividya Chandrasekhar, Gergey Alzaem Mousa, Joelle Chuang, Lilian Phu, Karen Y. Shih, Christopher M. Rose, John Kuriyan, Baris Bingol, Michael Rapé
{"title":"Reactive oxygen species control protein degradation at the mitochondrial import gate","authors":"Rachael McMinimy, Andrew G. Manford, Christine L. Gee, Srividya Chandrasekhar, Gergey Alzaem Mousa, Joelle Chuang, Lilian Phu, Karen Y. Shih, Christopher M. Rose, John Kuriyan, Baris Bingol, Michael Rapé","doi":"10.1016/j.molcel.2024.11.004","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.004","url":null,"abstract":"While reactive oxygen species (ROS) have long been known to drive aging and neurodegeneration, their persistent depletion below basal levels also disrupts organismal function. Cells counteract loss of basal ROS via the reductive stress response, but the identity and biochemical activity of ROS sensed by this pathway remain unknown. Here, we show that the central enzyme of the reductive stress response, the E3 ligase Cullin 2-FEM1 homolog B (CUL2<sup>FEM1B</sup>), specifically acts at mitochondrial TOM complexes, where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2<sup>FEM1B</sup> substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"14 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776465","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}
Molecular CellPub Date : 2024-12-05DOI: 10.1016/j.molcel.2024.11.001
Shaojie Cui, Linda Donnelly, Anchal Ghai, Samuel Achilefu, Jin Ye
{"title":"5H7c: A rabbit monoclonal antibody detecting ferroptotic cells","authors":"Shaojie Cui, Linda Donnelly, Anchal Ghai, Samuel Achilefu, Jin Ye","doi":"10.1016/j.molcel.2024.11.001","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.001","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Main text</h2>Ferroptosis, a cell death pathway triggered by iron-catalyzed peroxidation of phospholipids, has been implicated in both disease progression and cancer treatment.<sup>1</sup> A major challenge in studying ferroptosis has been the difficulty in detecting ferroptotic cells under physiological conditions, owing to the lack of a specific marker for ferroptosis.<sup>1</sup> This obstacle was recently overcome by our study published in <em>Molecular Cell</em>, which identified hyperoxidized PRDX3 as a specific marker for</section></section><section><section><h2>Declaration of interests</h2>The authors declare no competing interests.</section></section>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"14 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776510","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}
Molecular CellPub Date : 2024-12-05DOI: 10.1016/j.molcel.2024.11.011
Robert F. Harvey, Tuija Pöyry, Anne E. Willis
{"title":"Let’s (P-s)talk about specialized ribosomes","authors":"Robert F. Harvey, Tuija Pöyry, Anne E. Willis","doi":"10.1016/j.molcel.2024.11.011","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.011","url":null,"abstract":"In a recent study in <em>Cell</em>, Dopler et al.<span><span><sup>1</sup></span></span> show that a subpopulation of P-stalk-containing ribosomes (PSRs) are generated following exposure to cytokines, and the data suggest that PSRs are central mediators of translational reprogramming during the cytokine- and immune-response.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"109 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776462","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}
Molecular CellPub Date : 2024-12-05DOI: 10.1016/j.molcel.2024.11.017
Nathan P. Bullen, Aaron T. Whiteley
{"title":"Phages gain the upper hand in the metabolic arms race for NAD+","authors":"Nathan P. Bullen, Aaron T. Whiteley","doi":"10.1016/j.molcel.2024.11.017","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.017","url":null,"abstract":"Bacteria often defend against phage infection by deploying NADase effectors to degrade cellular NAD<sup>+</sup>, thereby halting both bacterial growth and phage replication. In a recent article in <em>Nature</em>, Osterman et al.<span><span><sup>1</sup></span></span> identify phage-encoded counterdefense pathways that reconstitute NAD<sup>+</sup> during infection, enabling phages to combat multiple unrelated antiphage systems.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776463","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}
Molecular CellPub Date : 2024-12-05DOI: 10.1016/j.molcel.2024.11.016
Yueyue Wang, Yalan Zhang, Wenxue Li, Barbora Salovska, Jianan Zhang, Tongqing Li, Hengyi Li, Yansheng Liu, Leonard K. Kaczmarek, Lajos Pusztai, Daryl E. Klein
{"title":"GABAA receptor π forms channels that stimulate ERK through a G-protein-dependent pathway","authors":"Yueyue Wang, Yalan Zhang, Wenxue Li, Barbora Salovska, Jianan Zhang, Tongqing Li, Hengyi Li, Yansheng Liu, Leonard K. Kaczmarek, Lajos Pusztai, Daryl E. Klein","doi":"10.1016/j.molcel.2024.11.016","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.016","url":null,"abstract":"The rare γ-aminobutyric acid type-A receptor (GABA<sub>A</sub>R) subunit π (GABRP) is highly expressed in certain cancers, where it stimulates growth through extracellular-regulated kinase (ERK) signaling by an uncharacterized pathway. To elucidate GABRP’s signaling mechanism, we determined cryoelectron microscopy (cryo-EM) structures of GABRP embedded in native nanodiscs, both in the presence and absence of GABA. Structurally, GABRP homopentamers closely resemble heteropentameric GABA<sub>A</sub>R anion channels, transitioning from a closed “resting” state to an open “active” state upon GABA binding. However, functional assays reveal that GABRP responds more like a type-B metabotropic receptor. At physiological concentrations of GABA, chloride flux is not detected. Rather, GABRP activates a G-protein-coupled pathway leading to ERK signaling. Ionotropic activity is only triggered at supraphysiological GABA concentrations, effectively decoupling it from GABRP’s signaling functions. These findings provide a structural and functional blueprint for GABRP, opening new avenues for targeted inhibition of GABA growth signals in GABRP-positive cancers.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"27 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776509","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}
Molecular CellPub Date : 2024-12-05DOI: 10.1016/j.molcel.2024.11.005
Dogancan Ozturan, Carl G. de Boer
{"title":"Silent silencers: Leave no trace","authors":"Dogancan Ozturan, Carl G. de Boer","doi":"10.1016/j.molcel.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.005","url":null,"abstract":"The regulatory mechanisms of silencers have remained poorly understood. In this issue, Hofbauer et al.<span><span><sup>1</sup></span></span> conduct a genome-wide screen in <em>Drosophila melanogaster</em> and reveal three silencer types that appear to work alone—without the need for combinatorial action, traditional chromatin marks, or open chromatin regions.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"12 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776511","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}
{"title":"p53 induces circFRMD4A to suppress cancer development through glycolytic reprogramming and cuproptosis","authors":"Quan Liao, Jun Deng, Jing Tong, Yu Gan, Weiwei Hong, Hanzhi Dong, Mingming Cao, Chen Xiong, Yajie Chen, Bangxiang Xie, Fu-Ying Yang, Aikede Alifu, Guang-Biao Zhou, Shenglin Huang, Jianping Xiong, Qian Hao, Xiang Zhou","doi":"10.1016/j.molcel.2024.11.013","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.013","url":null,"abstract":"Cuproptosis is a type of copper-induced cell death that mainly impacts cells relying on mitochondrial metabolism. Although p53 regulates glycolytic metabolism, its role in cuproptosis remains unclear. Here, we report that the circular RNA, circFRMD4A, is crucial for p53-mediated metabolic reprogramming and cuproptosis. CircFRMD4A originates from the transcript of <em>FRMD4A</em>, which is transcriptionally activated by p53, and the formation of circFRMD4A is facilitated by the RNA-binding protein EWSR1. CircFRMD4A functions as a tumor suppressor and enhances the sensitivity of cancer cells to elesclomol-induced cuproptosis. Mechanistic analysis reveals that circFRMD4A interacts with and inactivates the pyruvate kinase PKM2, leading to a decrease in lactate production and a redirection of glycolytic flux toward the tricarboxylic acid cycle. Finally, p53 agonists and elesclomol coordinately suppress the growth of cancer in a xenograft mouse model. Altogether, our study uncovers that p53 promotes glycolytic reprogramming and cuproptosis via circFRMD4A and suggests a potential combination strategy against cancers with wild-type p53.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"5 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763463","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}
Molecular CellPub Date : 2024-12-04DOI: 10.1016/j.molcel.2024.11.012
Dylan M. Parker, Devin Tauber, Roy Parker
{"title":"G3BP1 promotes intermolecular RNA-RNA interactions during RNA condensation","authors":"Dylan M. Parker, Devin Tauber, Roy Parker","doi":"10.1016/j.molcel.2024.11.012","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.012","url":null,"abstract":"Ribonucleoprotein (RNP) granules are biomolecular condensates requiring RNA and proteins to assemble. Stress granules are RNP granules formed upon increases in non-translating messenger ribonucleoprotein particles (mRNPs) during stress. G3BP1 and G3BP2 proteins are proposed to assemble stress granules through multivalent crosslinking of RNPs. We demonstrate that G3BP1 also has “condensate chaperone” functions, which promote the assembly of stress granules but are dispensable following initial condensation. Following granule formation, G3BP1 is dispensable for the RNA component of granules to persist <em>in vitro</em> and in cells when RNA decondensers are inactivated. These results demonstrate that G3BP1 functions as an “RNA condenser,” a protein that promotes intermolecular RNA-RNA interactions stabilizing RNA condensates, leading to RNP granule persistence. Moreover, the stability of RNA-only granules highlights the need for active mechanisms limiting RNP condensate stability and lifetime.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"12 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763211","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}
Molecular CellPub Date : 2024-12-03DOI: 10.1016/j.molcel.2024.11.009
Yanqing Liu, Joel A. Hrit, Alison A. Chomiak, Stephanie Stransky, Jordan R. Hoffman, Rochelle L. Tiedemann, Ashley K. Wiseman, Leena S. Kariapper, Bradley M. Dickson, Evan J. Worden, Christopher J. Fry, Simone Sidoli, Scott B. Rothbart
{"title":"DNA hypomethylation promotes UHRF1-and SUV39H1/H2-dependent crosstalk between H3K18ub and H3K9me3 to reinforce heterochromatin states","authors":"Yanqing Liu, Joel A. Hrit, Alison A. Chomiak, Stephanie Stransky, Jordan R. Hoffman, Rochelle L. Tiedemann, Ashley K. Wiseman, Leena S. Kariapper, Bradley M. Dickson, Evan J. Worden, Christopher J. Fry, Simone Sidoli, Scott B. Rothbart","doi":"10.1016/j.molcel.2024.11.009","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.009","url":null,"abstract":"Mono-ubiquitination of lysine 18 on histone H3 (H3K18ub), catalyzed by UHRF1, is a DNMT1 docking site that facilitates replication-coupled DNA methylation maintenance. Its functions beyond this are unknown. Here, we genomically map simultaneous increases in UHRF1-dependent H3K18ub and SUV39H1/H2-dependent H3K9me3 following DNMT1 inhibition. Mechanistically, transient accumulation of hemi-methylated DNA at CpG islands facilitates UHRF1 recruitment and E3 ligase activity toward H3K18. Notably, H3K18ub enhances SUV39H1/H2 methyltransferase activity and, in colon cancer cells, nucleates new H3K9me3 domains at CpG island promoters of DNA methylation-silenced tumor suppressor genes (TSGs). Disrupting UHRF1 enzyme activity prevents H3K9me3 accumulation while promoting PRC2-dependent H3K27me3 as a tertiary layer of gene repression in these regions. By contrast, disrupting H3K18ub-dependent SUV39H1/H2 activity enhances the transcriptional activating and antiproliferative effects of DNMT1 inhibition. Collectively, these findings reveal roles for UHRF1 and H3K18ub in regulating a hierarchy of repressive histone methylation signaling and rationalize a combination strategy for epigenetic cancer therapy.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"9 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760716","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}