Molecules and Cells最新文献

{"title":"Phosphorylation of eIF2α suppresses the impairment of GSH/NADPH homeostasis and mitigates the activation of cell death pathways, including ferroptosis, during ER stress","authors":"Hien Thi Le ,&nbsp;Yonghwan Kim ,&nbsp;Mi-Jeong Kim ,&nbsp;Seung Hwa Hyun ,&nbsp;Hyeeun Kim ,&nbsp;Su Wol Chung ,&nbsp;Yeonsoo Joe ,&nbsp;Hun Taeg Chung ,&nbsp;Dong-Myung Shin ,&nbsp;Sung Hoon Back","doi":"10.1016/j.mocell.2025.100210","DOIUrl":"10.1016/j.mocell.2025.100210","url":null,"abstract":"<div><div>eIF2α Phosphorylation helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. This study aims to elucidate the transcriptional regulation of glutathione (GSH) and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) homeostasis through eIF2α phosphorylation and its impact on cell death during ER stress. eIF2α phosphorylation-deficient (<em>A/A</em>) cells exhibited decreased expression of multiple genes involved in GSH synthesis and NADPH production, leading to an exacerbated depletion of both cellular and mitochondrial GSH, as well as mitochondrial NADPH, during ER stress. Impaired GSH homeostasis resulted from deficient expression of ATF4 and/or its dependent factor, Nrf2, which are key transcription factors in the antioxidant response during ER stress. In contrast, the exacerbation of NADPH depletion may primarily be attributed to the dysregulated expression of mitochondrial serine-driven 1-carbon metabolism pathway genes, which are regulated by an unidentified eIF2α phosphorylation-dependent mechanism during ER stress. Moreover, the eIF2α phosphorylation-ATF4 axis was responsible for upregulation of ferroptosis-inhibiting genes and downregulation of ferroptosis-activating genes upon ER stress. Therefore, ER stress strongly induced ferroptosis of <em>A/A</em> cells, which was significantly inhibited by treatments with cell-permeable GSH and the ferroptosis inhibitor ferrostatin-1. ATF4 overexpression suppressed impairment of GSH homeostasis in <em>A/A</em> cells during ER stress by promoting expression of downstream target genes. Consequently, ATF4 overexpression mitigated ferroptosis as well as apoptosis of <em>A/A</em> cells during ER stress. Our findings underscore the importance of eIF2α phosphorylation in maintaining GSH/NADPH homeostasis and inhibiting ferroptosis through ATF4 and unidentified eIF2α phosphorylation-dependent target(s)-mediated transcriptional reprogramming during ER stress.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 5","pages":"Article 100210"},"PeriodicalIF":3.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol Sulfate as a Negative Regulator of Cellular Cholesterol Homeostasis.","authors":"Le Ba Nam, Sung-Jin Kim, Tan Khanh Nguyen, Chang-Yun Jeong, June-Yong Lee, Jun-Seok Lee, Jeong Taeg Seo, Seok Jun Moon","doi":"10.1016/j.mocell.2025.100209","DOIUrl":"https://doi.org/10.1016/j.mocell.2025.100209","url":null,"abstract":"<p><p>Cholesterol sulfate (CS), one of the most abundant cholesterol derivatives, recently emerged as a key regulatory molecule in several physiological processes. Here, we demonstrate multiple mechanisms by which CS reduces intracellular cholesterol levels. CS promotes the proteasomal degradation of HMG-CoA reductase (HMGCR) by enhancing INSIG-mediated ubiquitination, thereby inhibiting cholesterol synthesis. In addition, CS blocks low-density lipoprotein (LDL) receptor endocytosis, reducing LDL cholesterol (LDL-C) uptake. CS further suppresses the proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2), a master transcription factor governing cholesterol synthesis and uptake. Using in vitro and in vivo models, we show that CS lowers cholesterol by targeting both the cholesterol synthesis and uptake pathways, while also modulating an important feedback loop via SREBP2. These findings highlight the potential of CS as a modulator of cholesterol metabolism, offering new therapeutic insights into cholesterol-related disorders.</p>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":" ","pages":"100209"},"PeriodicalIF":3.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover and caption","authors":"","doi":"10.1016/S1016-8478(25)00035-4","DOIUrl":"10.1016/S1016-8478(25)00035-4","url":null,"abstract":"","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 4","pages":"Article 100211"},"PeriodicalIF":3.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Board Members/Copyright","authors":"","doi":"10.1016/S1016-8478(25)00037-8","DOIUrl":"10.1016/S1016-8478(25)00037-8","url":null,"abstract":"","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 4","pages":"Article 100213"},"PeriodicalIF":3.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cryo-EM structures of mouse bestrophin 1 channel in closed and partially open conformations","authors":"Kwon-Woo Kim ,&nbsp;Euna Lee ,&nbsp;Ara Ko ,&nbsp;Junmo Hwang ,&nbsp;Kunwoong Park ,&nbsp;Byoung-Cheol Lee ,&nbsp;Ki Woo Kim ,&nbsp;Won-Jong Oh ,&nbsp;Kyuhyung Kim ,&nbsp;Hyun-Ho Lim","doi":"10.1016/j.mocell.2025.100208","DOIUrl":"10.1016/j.mocell.2025.100208","url":null,"abstract":"<div><div>Bestrophin 1 (BEST1) channels are calcium-activated Cl⁻ channels involved in diverse physiological processes, including gliotransmitter release in astrocytes. Although human and chicken BEST1 orthologs have been extensively studied, the structural and functional properties of mouse BEST1 (mBEST1) remain poorly understood. In this study, we characterized the structure-function of mBEST1-BF, a C–terminally tagged variant, using whole-cell patch-clamp recordings, surface biotinylation assays, and single-particle cryo-electron microscopy. Cryo-electron microscopy structural analysis of mBEST1-BF revealed closed and partially open conformations. Comparative analysis with human and chicken BEST1 orthologs highlighted conserved calcium-binding and gating mechanisms, with distinct features in mBEST1, including a wider aperture sufficient to accommodate dehydrated Cl⁻ ions and potential anion-binding sites near Val205 and Gln208 residues. The disordered C-terminal region of mBEST1 remains unresolved, suggesting it may require stabilizing factors for structural determination. Additionally, the autoinhibitory domain, which includes Ser354, likely plays a key role in regulating gating, with Ser354 potentially serving as a phosphorylation site that modulates channel activity. Our findings provide structural and functional insights into mBEST1 and suggest mechanisms underlying its unique gating and ion permeation properties.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 5","pages":"Article 100208"},"PeriodicalIF":3.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein-O-fucosylation of coreceptors may be required for Nodal signaling in Xenopus","authors":"Yeon-Jin Kim ,&nbsp;Seung-Joo Nho ,&nbsp;Soo Young Lee ,&nbsp;Chang-Yeol Yeo","doi":"10.1016/j.mocell.2025.100207","DOIUrl":"10.1016/j.mocell.2025.100207","url":null,"abstract":"<div><div>Nodal-related ligands of TGF-β family play pivotal roles for mesoderm induction and body axis formation during vertebrate early embryogenesis. Nodal ligands are distinct from most other TGF-β ligands family as they require EGF-CFC factors as coreceptors for signaling, in addition to their cognate type I and type II TGF-β receptors. In amphibian <em>Xenopus laevis</em> embryos, 5 <em>Nodal-related</em> genes (<em>Xnr1/2/4/5/6</em>) and 2 <em>EGF-CFC</em> genes (<em>XCR1</em>, <em>XCR3</em>) play roles in mesoderm induction and the accumulation of phosphorylated Smad2, while in mammalian embryos, 1 <em>Nodal</em> gene and 1 <em>EGF-CFC</em> gene (<em>Cripto</em>) play roles during mesoderm induction. Mammalian EGF-CFC factors are reported to be <em>O</em>-fucosylated at a conserved threonine residue of the EGF-like motif by protein-<em>O</em>-fucosyltransferase 1 (Pofut1), but this <em>O</em>-fucose modification is shown to be dispensable for Nodal signaling in mammalian embryos. In this study, we investigated the developmental roles of <em>Xenopus laevis Pofut1</em> (<em>XPofut1</em>) and its potential function in Nodal signaling. We found that morpholino antisense-mediated knockdown of <em>XPofut1</em> causes reduction of Smad2 phosphorylation in late blastula and axial truncation in neurula. We also found that the <em>O</em>-fucosyltransferase activity of XPofut1 is important in the marginal zone, but not in the vegetal pole region, of blastula. Interestingly, <em>XPofut1</em> is necessary for Smad2 phosphorylation induced by Xnr1 or Xnr2, but not by Xnr5 or Xnr6. Among the Nodal signaling components, only EGF-CFC factors are known to be modified by Pofut1. Therefore, based on our current observation, we propose that XPofut1 regulates signaling of a subset of nodal ligands in pregastrulation embryos possibly through modulating the function of EGF-CFC factors.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 5","pages":"Article 100207"},"PeriodicalIF":3.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Principles and therapeutics of cancer","authors":"Yoontae Lee","doi":"10.1016/j.mocell.2025.100201","DOIUrl":"10.1016/j.mocell.2025.100201","url":null,"abstract":"","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 5","pages":"Article 100201"},"PeriodicalIF":3.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Omics technologies as powerful approaches to unravel colorectal cancer complexity and improve its management","authors":"Zaynab Fatfat ,&nbsp;Marwa Hussein ,&nbsp;Maamoun Fatfat ,&nbsp;Hala Gali-Muhtasib","doi":"10.1016/j.mocell.2025.100200","DOIUrl":"10.1016/j.mocell.2025.100200","url":null,"abstract":"<div><div>Colorectal cancer (CRC) continues to rank among the deadliest and most prevalent cancers worldwide, necessitating an innovative and comprehensive approach that addresses this serious health challenge at various stages, from screening and diagnosis to treatment and prognosis. As CRC research progresses, the adoption of an omics-centered approach holds transformative potential to revolutionize the management of this disease. Advances in omics technologies encompassing genomics, transcriptomics, proteomics, metabolomics, and epigenomics allow to unravel the oncogenic alterations at these levels, elucidating the intricacies and the heterogeneous nature of CRC. By providing a comprehensive molecular landscape of CRC, omics technologies enable the discovery of potential biomarkers for early non-invasive detection of CRC, definition of CRC subtypes, prediction of its staging, prognosis, and overall survival of CRC patients. They also allow the identification of potential therapeutic targets, prediction of drug response, tracking treatment efficacy, detection of residual disease and cancer relapse, and deciphering the mechanisms of drug resistance. Moreover, they allow the distinction of non-metastatic CRC patients from metastatic ones as well as the stratification of metastatic risk. Importantly, omics technologies open up new opportunities to establish molecular-based criteria to guide the selection of effective treatment paving the way for the personalization of therapy for CRC patients. This review consolidates current knowledge on the omics-based preclinical discoveries in CRC research emphasizing the significant potential of these technologies to improve CRC screening, diagnosis, and prognosis and promote the implementation of personalized medicine to ultimately reduce CRC prevalence and mortality.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 5","pages":"Article 100200"},"PeriodicalIF":3.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover and caption","authors":"","doi":"10.1016/S1016-8478(25)00026-3","DOIUrl":"10.1016/S1016-8478(25)00026-3","url":null,"abstract":"","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 3","pages":"Article 100202"},"PeriodicalIF":3.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Board Members/Copyright","authors":"","doi":"10.1016/S1016-8478(25)00028-7","DOIUrl":"10.1016/S1016-8478(25)00028-7","url":null,"abstract":"","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 3","pages":"Article 100204"},"PeriodicalIF":3.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}