Cell reports最新文献

Targeting both the enzymatic and non-enzymatic functions of DHODH as a therapeutic vulnerability in c-Myc-driven cancer.

IF 7.5 1区生物学

Cell reports Pub Date : 2025-02-19 DOI: 10.1016/j.celrep.2025.115327

Qiang Zhang, Kaisa Cui, Yue Kong, Jing Yu, Zhanhao Luo, Xiaoya Yang, Liang Gong, Yanchun Xie, Jiuxiu Lin, Chen Liu, Zongjin Zhang, Yugeng Liu, Bingxin Liu, Dayi Liang, Wanyi Zeng, Zhen He, Ping Lan

{"title":"Targeting both the enzymatic and non-enzymatic functions of DHODH as a therapeutic vulnerability in c-Myc-driven cancer.","authors":"Qiang Zhang, Kaisa Cui, Yue Kong, Jing Yu, Zhanhao Luo, Xiaoya Yang, Liang Gong, Yanchun Xie, Jiuxiu Lin, Chen Liu, Zongjin Zhang, Yugeng Liu, Bingxin Liu, Dayi Liang, Wanyi Zeng, Zhen He, Ping Lan","doi":"10.1016/j.celrep.2025.115327","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115327","url":null,"abstract":"c-Myc (Myc)-driven cancers exhibit aggressive phenotypes and therapeutic resistance. Here, integrating CRISPR-Cas9 screening, we identify dihydroorotate dehydrogenase (DHODH) as a promising target in Myc-driven cancer. Mechanistically, DHODH interacts with Myc to stabilize it independently of its enzymatic activity, thereby antagonizing SKP2-mediated polyubiquitination and proteasomal degradation. EN4, a Myc transcriptional activity inhibitor, disrupts DHODH-Myc interaction, promoting Myc degradation via SKP2. Additionally, Myc transcriptionally activates DHODH, enhancing pyrimidine biosynthesis and ferroptosis defense, processes dependent on DHODH enzymatic activity. Clinically, DHODH positively correlates with Myc, activating pyrimidine metabolism and ferroptosis defense in Myc-driven cancers. Hyperactivation of the DHODH-Myc axis is linked to colorectal cancer progression and poor prognosis. Therapeutically, combining EN4 with a DHODH enzymatic inhibitor demonstrates potent antitumor efficacy in Myc-driven colorectal cancer. Overall, our findings elucidate the metabolic and non-metabolic roles of DHODH in Myc-driven cancer, underscoring its dual potential as a therapeutic target addressing both enzymatic and non-enzymatic functions.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115327"},"PeriodicalIF":7.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467215","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

HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation.

IF 7.5 1区生物学

Cell reports Pub Date : 2025-02-19 DOI: 10.1016/j.celrep.2025.115339

Guangyan Yang, Chuanrui Ma, Yuanli Chen, Jiaqing Xiang, Lixing Li, Yanchun Li, Lin Kang, Zhen Liang, Shu Yang

{"title":"HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation.","authors":"Guangyan Yang, Chuanrui Ma, Yuanli Chen, Jiaqing Xiang, Lixing Li, Yanchun Li, Lin Kang, Zhen Liang, Shu Yang","doi":"10.1016/j.celrep.2025.115339","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115339","url":null,"abstract":"Lipid accumulation in renal tubules is a major determinant of diabetic kidney disease (DKD), and activation of SREBPs plays a central role in this process. Our study aims to explore whether HSPA8, a molecular chaperone, is the master regulator of INSIG/SREBPs function in DKD. Here, we show that tubular epithelial cell (TEC)-specific knockout of HSPA8 upregulates the phosphorylation of INSIG1 and INSIG2, which disrupts the interaction between INSIG proteins and SCAP, leading to SREBP activation. TEC-specific overexpression of HSPA8 restrains these changes. INSIG1/2 can be phosphorylated by protein kinase R (PKR), while HSPA8 recognizes PKR and recruits the E3 ubiquitin ligase to promote PKR ubiquitination and degradation. Under temporary hyperglycemic stimulation, SREBP1 transcriptionally activates HSPA8 expression. Conversely, persistent hyperglycemia reduces HSPA8 levels via promoting NF-κB-mediated transcriptional inhibition of HSPA8. Collectively, these findings indicate that the molecular chaperone HSPA8 serves as a negative feedback regulator of SREBPs, lipogenesis, and DKD development.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115339"},"PeriodicalIF":7.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467211","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

ARHGEF18 is a flow-responsive exchange factor controlling endothelial tight junctions and vascular leakage.

IF 7.5 1区生物学

Cell reports Pub Date : 2025-02-19 DOI: 10.1016/j.celrep.2025.115288

Surya Prakash Rao Batta, Marc Rio, Corentin Lebot, Céline Baron-Menguy, Maxence Bodet, Reda Moutaoukil, Robin Le Ruz, Ibtissam Babahnini, Gervaise Loirand, Anne-Clémence Vion

{"title":"ARHGEF18 is a flow-responsive exchange factor controlling endothelial tight junctions and vascular leakage.","authors":"Surya Prakash Rao Batta, Marc Rio, Corentin Lebot, Céline Baron-Menguy, Maxence Bodet, Reda Moutaoukil, Robin Le Ruz, Ibtissam Babahnini, Gervaise Loirand, Anne-Clémence Vion","doi":"10.1016/j.celrep.2025.115288","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115288","url":null,"abstract":"The shear stress resulting from blood flow is a major regulator of endothelial cell (EC) biology and morphology. Rho protein-mediated cytoskeleton remodeling is an early and essential step of EC responses to flow. However, how Rho protein signaling is controlled by shear stress remains unclear. Here we demonstrate that phosphorylation, activity, and expression of the Rho nucleotide exchange factor (RhoGEF) ARHGEF18 in ECs are modulated by the magnitude of shear stress. When phosphorylated, ARHGEF18 interacts with tight junctions; participates in EC elongation, alignment, and migration; and allows the maintenance of the endothelial barrier under physiological flow conditions. In mice, ARHGEF18 is involved in tight junction formation, flow response of ECs, and the control of vascular permeability. Together, our results identified ARHGEF18 as the first flow-sensitive RhoGEF in ECs, whose activity is essential for the maintenance of intercellular junctions and the control of vascular permeability in vivo.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115288"},"PeriodicalIF":7.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467209","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

Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.

IF 7.5 1区生物学

Cell reports Pub Date : 2025-02-19 DOI: 10.1016/j.celrep.2025.115386

Mari Aikio, Hana M Odeh, Heike J Wobst, Bo Lim Lee, Úna Chan, Jocelyn C Mauna, Korrie L Mack, Bradley Class, Thomas A Ollerhead, Alice F Ford, Edward M Barbieri, Ryan R Cupo, Lauren E Drake, Joshua L Smalley, Yuan-Ta Lin, Stephanie Lam, Reuben Thomas, Nicholas Castello, Ashmita Baral, Jenna N Beyer, Mohd A Najar, John Dunlop, Aaron D Gitler, Ashkan Javaherian, Julia A Kaye, George M Burslem, Dean G Brown, Christopher J Donnelly, Steven Finkbeiner, Stephen J Moss, Nicholas J Brandon, James Shorter

引用次数: 0

Structural insights into prolactin-releasing peptide receptor signaling and G-protein coupling selectivity.

IF 7.5 1区生物学

Cell reports Pub Date : 2025-02-19 DOI: 10.1016/j.celrep.2025.115337

Zhangsong Wu, Chen Qiu, Yiming Liu, Xiaoyi Yan, Qiaohui Li, Shirui Jiang, Jun Xu, Xin Pan, Fang Ye, Zhiyi Zhang, Peiruo Ning, Binghao Zhang, Lezhi Xu, Bangning Cheng, Xufu Xiang, Chungen Qian, Yang Du, Geng Chen

{"title":"Structural insights into prolactin-releasing peptide receptor signaling and G-protein coupling selectivity.","authors":"Zhangsong Wu, Chen Qiu, Yiming Liu, Xiaoyi Yan, Qiaohui Li, Shirui Jiang, Jun Xu, Xin Pan, Fang Ye, Zhiyi Zhang, Peiruo Ning, Binghao Zhang, Lezhi Xu, Bangning Cheng, Xufu Xiang, Chungen Qian, Yang Du, Geng Chen","doi":"10.1016/j.celrep.2025.115337","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115337","url":null,"abstract":"Prolactin-releasing peptide receptor (PrRPR), a notable member of the class A peptide-GPCR (G-protein-coupled receptor) family, regulates diverse physiology functions upon activation by PrRP. Herein, we reveal that PrRPR could engage with not only the Gq/11 pathway but also the Gi/o pathway. We further resolve the structures of the PrRPR-Gq and PrRPR-Gi complexes using cryoelectron microscopy (cryo-EM), with PrRP31 as the endogenous ligand. These high-resolution structures enhance our understanding of PrRPR-ligand interactions, aiding the development of targeted drugs aiming at this crucial peptide-receptor system. Comparing these structures with counterparts of other RF-amide peptide receptors accentuates the crucial function of the RF-amide motif in activating receptors and sheds light on the universal mechanism for RF-amide motif detection by RF-amide receptors. Furthermore, structural and functional analysis indicates that conformational alterations in the intracellular loops (ICLs), along with the \"wavy hook\" of Gα, may explain the selective coupling of G proteins in PrRPR signaling.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115337"},"PeriodicalIF":7.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467213","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

Overfeeding induces adipose tissue release of distinct mitochondria.

IF 7.5 1区生物学

Cell reports Pub Date : 2025-02-18 DOI: 10.1016/j.celrep.2025.115318

Joshua H Goodman, Chloé Berland, Rajesh K Soni, Anthony W Ferrante

引用次数: 0

An Aurora kinase A-BOD1L1-PP2A B56 axis promotes chromosome segregation fidelity.

IF 7.5 1区生物学

Cell reports Pub Date : 2025-02-18 DOI: 10.1016/j.celrep.2025.115317

Thomas J Kucharski, Irma M Vlasac, Tatiana Lyalina, Martin R Higgs, Brock C Christensen, Susanne Bechstedt, Duane A Compton

{"title":"An Aurora kinase A-BOD1L1-PP2A B56 axis promotes chromosome segregation fidelity.","authors":"Thomas J Kucharski, Irma M Vlasac, Tatiana Lyalina, Martin R Higgs, Brock C Christensen, Susanne Bechstedt, Duane A Compton","doi":"10.1016/j.celrep.2025.115317","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115317","url":null,"abstract":"Cancer cells are often aneuploid and frequently display elevated rates of chromosome mis-segregation, called chromosomal instability (CIN). CIN is caused by hyperstable kinetochore-microtubule (K-MT) attachments that reduce the correction efficiency of erroneous K-MT attachments. UMK57, a chemical agonist of the protein MCAK (mitotic centromere-associated kinesin), improves chromosome segregation fidelity in CIN cancer cells by destabilizing K-MT attachments, but cells rapidly develop resistance. To determine the mechanism, we performed unbiased screens, which revealed increased phosphorylation in cells adapted to UMK57 at Aurora kinase A phosphoacceptor sites on BOD1L1 (protein biorientation defective 1-like-1). BOD1L1 depletion or Aurora kinase A inhibition eliminated resistance to UMK57. BOD1L1 localizes to spindles/kinetochores during mitosis, interacts with the PP2A phosphatase, and regulates phosphorylation levels of kinetochore proteins, chromosome alignment, mitotic progression, and fidelity. Moreover, the BOD1L1 gene is mutated in a subset of human cancers, and BOD1L1 depletion reduces cell growth in combination with clinically relevant doses of Taxol or Aurora kinase A inhibitor.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 2","pages":"115317"},"PeriodicalIF":7.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456997","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

Structural basis of promiscuous inhibition of Listeria virulence activator PrfA by oligopeptides.

IF 7.5 1区生物学

Cell reports Pub Date : 2025-02-17 DOI: 10.1016/j.celrep.2025.115290

Tobias Hainzl, Mariela Scortti, Cecilia Lindgren, Christin Grundström, Emilia Krypotou, José A Vázquez-Boland, A Elisabeth Sauer-Eriksson

{"title":"Structural basis of promiscuous inhibition of Listeria virulence activator PrfA by oligopeptides.","authors":"Tobias Hainzl, Mariela Scortti, Cecilia Lindgren, Christin Grundström, Emilia Krypotou, José A Vázquez-Boland, A Elisabeth Sauer-Eriksson","doi":"10.1016/j.celrep.2025.115290","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115290","url":null,"abstract":"The facultative pathogen Listeria monocytogenes uses a master regulator, PrfA, to tightly control the fitness-costly expression of its virulence factors. We found that PrfA activity is repressed via competitive occupancy of the binding site for the PrfA-activating cofactor, glutathione, by exogenous nutritional oligopeptides. The inhibitory peptides show different sequence and physicochemical properties, but how such a wide variety of oligopeptides can bind PrfA was unclear. Using crystal structure analysis of PrfA complexed with inhibitory tri- and tetrapeptides, we show here that the binding promiscuity is due to the ability of PrfA β5 in the glutathione-binding inter-domain tunnel to establish parallel or antiparallel β sheet-like interactions with the peptide backbone. Spacious tunnel pockets provide additional flexibility for unspecific peptide accommodation while providing selectivity for hydrophobic residues. Hydrophobic contributions from two adjacent peptide residues appear to be critical for efficient PrfA inhibitory binding. In contrast to glutathione, peptide binding prevents the conformational change required for the correct positioning of the DNA-binding helix-turn-helix motifs of PrfA, effectively inhibiting virulence gene expression.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 2","pages":"115290"},"PeriodicalIF":7.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457003","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

Luminescent sensing of conformational integrin activation in living cells.

IF 7.5 1区生物学

Cell reports Pub Date : 2025-02-17 DOI: 10.1016/j.celrep.2025.115319

Giulia Villari, Noemi Gioelli, Marta Gino, Heng Zhang, Kelly Hodge, Francesca Cordero, Sara Zanivan, Jieqing Zhu, Guido Serini

{"title":"Luminescent sensing of conformational integrin activation in living cells.","authors":"Giulia Villari, Noemi Gioelli, Marta Gino, Heng Zhang, Kelly Hodge, Francesca Cordero, Sara Zanivan, Jieqing Zhu, Guido Serini","doi":"10.1016/j.celrep.2025.115319","DOIUrl":"10.1016/j.celrep.2025.115319","url":null,"abstract":"Integrins are major receptors for secreted extracellular matrix, playing crucial roles in physiological and pathological contexts, such as angiogenesis and cancer. Regulation of the transition between inactive and active conformation is key for integrins to fulfill their functions, and pharmacological control of those dynamics may have therapeutic applications. We create and validate a prototypic luminescent β1 integrin activation sensor (β1IAS) by introducing a split luciferase into an activation reporting site between the βI and the hybrid domains. As a recombinant protein in both solution and living cells, β1IAS accurately reports β1 integrin activation in response to (bio)chemical and physical stimuli. A short interfering RNA (siRNA) high-throughput screening on live β1IAS knockin endothelial cells unveils hitherto unknown regulators of β1 integrin activation, such as β1 integrin inhibitors E3 ligase Pja2 and vascular endothelial growth factor B (VEGF-B). This split-luciferase-based strategy provides an in situ label-free measurement of integrin activation and may be applicable to other β integrins and receptors.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 2","pages":"115319"},"PeriodicalIF":7.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448333","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

Identification of CCL3 as a Schwann cell chemotactic factor essential for nerve regeneration.

IF 7.5 1区生物学

Cell reports Pub Date : 2025-02-16 DOI: 10.1016/j.celrep.2025.115322

Lucie Van Emmenis, Guillem Mòdol-Caballero, Elizabeth Harford-Wright, Alex Power, Anne-Laure Cattin, Ian J White, Giulia Casal, Inês Boal-Carvalho, Clare L Bennett, Alison C Lloyd

{"title":"Identification of CCL3 as a Schwann cell chemotactic factor essential for nerve regeneration.","authors":"Lucie Van Emmenis, Guillem Mòdol-Caballero, Elizabeth Harford-Wright, Alex Power, Anne-Laure Cattin, Ian J White, Giulia Casal, Inês Boal-Carvalho, Clare L Bennett, Alison C Lloyd","doi":"10.1016/j.celrep.2025.115322","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115322","url":null,"abstract":"Peripheral nerves regenerate following injury, in contrast to those of the central nervous system. This involves the collective migration of Schwann cell (SC) cords, which transport regrowing axons across the wound site. The SC cords migrate along a newly formed vasculature, which bridges the wound site in response to vascular endothelial growth factor, secreted by hypoxic macrophages. However, the directional signals by which SC cords navigate the long distances across the wound, in the absence of those that guide axons during development, remain unknown. Here, we identify CCL3 as the SC chemotactic factor, secreted by hypoxic macrophages, responsible for this process. We show that CCL3 promotes collective SC migration and axonal regrowth in vivo and, using genetic mouse models and widely used CCL3 inhibitors, that CCL3 is essential for effective nerve regeneration. These findings have therapeutic implications for both promoting nerve repair and inhibiting the aberrant nerve growth associated with trauma and disease.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 2","pages":"115322"},"PeriodicalIF":7.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439994","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