The FASEB Journal最新文献

{"title":"Identification of the potential role of S1PR1 in adult moyamoya disease based on multiple bioinformatics analysis and experimental verification","authors":"Jiabin Zhou,&nbsp;Yu Lei,&nbsp;Shilin Zhang,&nbsp;Renwu Qin,&nbsp;Yuhan Liu,&nbsp;Dongye Yi","doi":"10.1096/fj.202401445R","DOIUrl":"https://doi.org/10.1096/fj.202401445R","url":null,"abstract":"<p>Moyamoya disease (MMD) is a chronic occlusive cerebrovascular ailment with a progressively rising incidence, yet its precise etiology and pathogenesis remain elusive. Adult MMD-related datasets GSE189993 and GSE157628 were procured from the GEO database for screening of differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was employed to unveil the most significant module associated with MMD. Least absolute shrinkage and selection operator (LASSO) logistic regression was used to identify and validate diagnostic markers for MMD. CIBERSORT and ssGSEA analyses were conducted to estimate immune cell infiltration in MMD vessels. In vitro experiments were performed to validate the biological functions of Sphingosine-1-phosphate receptor 1 (S1PR1) in mouse aortic smooth muscle cells (MOVAS). A total of 436 DEGs were identified from GSE189993, comprising 202 up-regulated genes and 234 down-regulated genes. Within the green-yellow module, 87 genes overlapped with DEGs, and 6 genes were identified by Cytoscape as key factors in the pathophysiology of MMD, namely, platelet endothelial cell adhesion molecule 1 (PECAM1), von Willebrand factor (VWF), intercellular cell adhesion molecule 1 (ICAM1), vascular endothelial growth factor C (VEGFC), tissue-type plasminogen activator (PLAT), and S1PR1. Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses also showed that key genes were mainly involved in endothelial cells and cell adhesion-related biological function. About 13 diagnostic genes were obtained by the LASSO regression algorithm, with S1PR1 emerging as a hub gene demonstrating good diagnostic performance in both the test set and validation set. Finally, we validated that overexpression of S1PR1 spurred viability, proliferation, and cell division in mouse aortic smooth muscle cells (MOVAS) and human cerebral vascular smooth muscle cells (HCVSMC) by activating the PI3K/AKT signaling pathway. S1PR1 has been identified as a hub gene for MMD. S1PR1 overexpression has been linked to enhanced cell division and proliferation in vitro, suggesting its potential as a therapeutic target for adult MMD.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 6","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into the single-cell transcriptome characteristics of porcine endometrium with embryo loss","authors":"Tingting Chu,&nbsp;Yadan Jin,&nbsp;Guofang Wu,&nbsp;Jinyi Liu,&nbsp;Shiduo Sun,&nbsp;Yuxuan Song,&nbsp;Guoliang Zhang","doi":"10.1096/fj.202402212RR","DOIUrl":"https://doi.org/10.1096/fj.202402212RR","url":null,"abstract":"<p>Reproductive disorders are a concern in the pig industry. Successful gestation processes are closely related to a suitable endometrial microenvironment, and the physiological mechanisms leading to failed pregnancy during the peri-implantation period remain unclear. We constructed single-cell transcriptome profiles of peri-implantation embryo loss and successful gestation endometrial tissues and identified 22 cell subpopulations, with epithelial and stromal cells being the predominant endometrial cell types. The two tissues showed marked differences in cell type composition, especially among epithelial cell subpopulations. We also observed functional differences between epithelial and stromal cells in tissues from embryonic loss and successful gestation, as well as the expression levels and differentiation trajectories of genes associated with embryo attachment and endometrial receptivity in epithelial and stromal cells. The results of cell communication interactions analysis showed that ciliated cells were more active in endometrial tissue with embryo loss, and there were differences in the types of endometrial cells with major roles in embryo loss and embryo implantation successful tissues for bone morphogenic protein, insulin-like growth factor, and transforming growth factor-β signaling networks associated with embryo implantation. In addition, we compared the functional differences in immune cells between the two tissue types and the expression levels of genes related to the inflammatory microenvironment. Overall, the present study revealed the molecular features of endometrial cell transcription in embryo-lost endometrial tissues, providing deeper insights into the endometrial microenvironment of reproductive disorders, which may inform the etiological, diagnostic, and therapeutic studies of reproductive disorders.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 6","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202402212RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ovarian aging-associated downregulation of GPX4 expression regulates ovarian follicular development by affecting granulosa cell functions and oocyte quality","authors":"Jingyi Hu,&nbsp;Huihui Wang,&nbsp;Junnan Fang,&nbsp;Ran Jiang,&nbsp;Yue Kong,&nbsp;Tongwei Zhang,&nbsp;Guang Yang,&nbsp;Haixia Jin,&nbsp;Senlin Shi,&nbsp;Ning Song,&nbsp;Lin Qi,&nbsp;Xianju Huang,&nbsp;Zhaoting Wu,&nbsp;Guidong Yao","doi":"10.1096/fj.202401580RR","DOIUrl":"https://doi.org/10.1096/fj.202401580RR","url":null,"abstract":"<p>In the physiological state, female fertility declines with age, as evidenced by a steady decline in oocyte quantity and quality. Aging of the first organ, the ovary, is accompanied by increased oxidative stress levels in the ovary, causing a decline in the ovarian reserve and follicular atresia. Ferroptosis is a novel mode of programmed cell death discovered in recent years and is involved in the onset and development of various diseases. To investigate whether ferroptosis regulates ovarian aging, we first examined granulosa cells from patients with a normal ovarian reserve, decreased ovarian reserve (DOR), and advanced age (Aged). <i>GPX4</i>, a key gene involved in ferroptosis, was identified. The marker of its activity, glutathione (GSH), was significantly downregulated in granulosa cells from the DOR and Aged groups. Transmission electron microscopy confirmed abnormal changes in mitochondrial morphology in granulosa cells from the DOR and Aged groups. In vitro, granulosa cell culture results showed that ferroptosis inducers inhibited cell growth by downregulating GPX4 expression. In contrast, ferroptosis inhibitors reversed the inhibitory effects of ferroptosis on granulosa cell growth by upregulating GPX4 expression. The results of mice in vivo experiments showed that the expression level of GPX4 was significantly decreased in the oocytes of aged mice and that Fer-1, an inhibitor of ferroptosis, reversed the decrease in the number of oocytes retrieved and the quality of oocytes in aged mice. Cyclophosphamide (CTX) was used to generate a mouse model of premature ovarian failure. The results showed that Fer-1 treatment significantly restored the inhibitory effect of CTX on GPX4 expression in the cumulus cells and partially reversed the adverse effects of CTX on the follicular reserve in the ovaries, the number of oocytes retrieved, and the quality of the oocytes in mice. The study findings suggest that ferroptosis is involved in regulating ovarian aging and that <i>GPX4</i> is a key gene in regulating ovarian follicle development and ferroptosis and a potential key target for treating ovarian aging.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 6","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143638681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Colorectal cancer cell-derived extracellular vesicles trigger macrophage production of IL6 through activating STING signaling to drive metastasis","authors":"Fangqi Hu,&nbsp;Weipeng Gong,&nbsp;Bao Song,&nbsp;Song Zhang","doi":"10.1096/fj.202402757RR","DOIUrl":"https://doi.org/10.1096/fj.202402757RR","url":null,"abstract":"<p>Emerging evidence shows that extracellular vesicles (EVs)-mediated cargo shuttling between different kinds of cells constantly occurs in the tumor microenvironment, leading to the progression of a variety of cancers, but the biological role of DNA enriched in EVs has not been fully elucidated. Here, nuclear chromatin-originated DNA fragments were identified in human serum-derived EVs and exhibited a mild increase in the colorectal cancer patient group, unveiling their potential as a biomarker for cancer diagnosis. Molecular experiments showed that chromatin and mitochondrial DNA fragments adhered to the outer membrane of EVs were released from colorectal cancer cells and transported into macrophages where they stimulated STING signaling cascades, resulting in enhanced STAT1 phosphorylation and IL6 production. Further experiments revealed that STAT1 functioned as a potential IL6 transcription regulator through directly locating at its promoter regions to facilitate IL6 expression in macrophages. In the tumor microenvironment, the accumulated IL6 released by macrophages, in turn, provoked colorectal cancer cell epithelial to mesenchymal transition (EMT) through activating IL6R/STAT3 signaling. Our findings highlighted the importance of DNA carried by EVs in shaping the tumor environment and revealed their potential as a clinical diagnostic biomarker for colorectal cancer.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 6","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143638992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uric acid promotes aortic valve calcification via mediating valve interstitial cell osteogenic differentiation and endothelial dysfunction","authors":"Jialiang Zhang,&nbsp;Wenhua Lei,&nbsp;Jing Zhou,&nbsp;Yaoyu Zhang,&nbsp;Fangyang Huang,&nbsp;Mao Chen","doi":"10.1096/fj.202402831R","DOIUrl":"https://doi.org/10.1096/fj.202402831R","url":null,"abstract":"<p>Aortic valve calcification is a lethal valvular heart disease lacking effective drug therapy. However, whether uric acid is involved in the development of aortic valve calcification is unclear. Two-sample Mendelian randomization (MR) analyses confirmed the causal relationship between uric acid and valvular heart disease. Uric acid levels were assessed in aortic valve tissue from patients with/without aortic valve calcification. To investigate the impact of hyperuricemia on aortic valve calcification, apolipoprotein E knockout (ApoE^−/−) mice fed a high-fat diet (HFD) were also given an adenine diet, with some receiving allopurinol in their drinking water. RNA sequencing was performed on valve interstitial cells (VICs) and endothelial cells (VECs) with/without uric acid. MR analysis has revealed a causal effect of uric acid levels on valvular heart disease. Furthermore, our clinical data indicate a positive correlation between elevated serum uric acid levels and aortic valve calcium score. Specifically, uric acid levels were upregulated in calcified valves. In ApoE^−/− mice, an adenine-diet-induced hyperuricemia accelerated aortic valve calcification. RNA sequencing analysis demonstrated that uric acid-promoted osteogenic differentiation, primarily through the activation of hypoxia-inducible factor-1alpha (HIF-α). Additionally, uric acid impaired endothelial barrier function by activating HIF-α, resulting in increased macrophage infiltration in ApoE^−/− mice. Inhibiting HIF-1α suppressed osteogenic differentiation and reduced endothelial injury both in vitro and in vivo in the presence of uric acid. This study reveals a new role of hyperuricemia in aortic valve calcification, suggesting uric acid-lowering drugs or HIF-1α inhibition as potential treatments for associated aortic valve calcification.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 6","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological regulators of Hippo pathway: Advances and challenges of drug development","authors":"Zhaobai Lao,&nbsp;Xin Chen,&nbsp;Bin Pan,&nbsp;Bin Fang,&nbsp;Wanlei Yang,&nbsp;Yu Qian","doi":"10.1096/fj.202401895RR","DOIUrl":"https://doi.org/10.1096/fj.202401895RR","url":null,"abstract":"<p>The Hippo signaling pathway is crucial in regulating organ size, tumor progression, tissue regeneration, and bone homeostasis. Inactivation of the Hippo pathway results in the nuclear translocation and activation of YAP/TAZ. This activation not only promotes tumor progression but also enhances tissue regeneration, wound healing, and maintenance of bone stability Although its discovery occurred over two decades ago, developing effective inhibitors or activators for the Hippo pathway remains challenging. Recently, however, the pace of advancements in developing Hippo signaling-related agonists and antagonists has accelerated, with some drugs that target TEAD advancing to clinical trials and showing promise for treating related diseases. This review summarizes the progress in research on Hippo signaling-related agonists and inhibitors, offering an in-depth analysis of their regulatory mechanisms, pharmacological properties, and potential in vivo applications.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 6","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401895RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143638682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary effects on the retina of hamsters","authors":"Nicole El-Darzi,&nbsp;Natalia Mast,&nbsp;Yong Li,&nbsp;Irina A. Pikuleva","doi":"10.1096/fj.202403390R","DOIUrl":"https://doi.org/10.1096/fj.202403390R","url":null,"abstract":"<p>The retina is a sensory tissue in the back of the eye, which captures visual information and relays it to the brain. The retinal pigment epithelium separates the neural retina from the choroidal (systemic) circulation and is thereby exposed to circulating lipoprotein particles. Herein, we used hamsters and conducted various retinal evaluations of animals fed either a normal diet or a Western-type diet (WTD). Prior to evaluations, hamsters were injected with indocyanine green (ICG), a fluorescent dye that binds to various proteins and lipids in the systemic circulation. The WTD increased plasma levels of total and HDL cholesterol 1.8- and 2.1-fold, respectively, and led to additional HDL₂ and HDL₃ subpopulations. The diet also increased the ICG fluorescence in the retinal pigment epithelium and the underlying choroidal circulation on histological tracking and altered retinal protein abundance as assessed by proteomics. Functional enrichments were found in the retinal gene expression, energy production, intracellular transport, cytoskeleton- and synapse-related processes, and protein ubiquitination. The biochemical basis linking the WTD, retinal energy production, and retinal neurotransmission was suggested as well. The data obtained were then compared with those from our previous investigations of hamsters and different mouse genotypes. We identified common retinal processes that can be affected by circulating lipoprotein particles regardless of the mechanism by which their levels and subpopulations were altered (through diet or genetic modification). Thus, we obtained novel mechanistic insights into how lipids in the systemic circulation can affect the retina.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 6","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403390R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143638680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Limosilactobacillus reuteri promotes the expression and secretion of enteroendocrine- and enterocyte-derived hormones","authors":"Sara C. Di Rienzi,&nbsp;Heather A. Danhof,&nbsp;Micah D. Forshee,&nbsp;Ari Roberts,&nbsp;Robert A. Britton","doi":"10.1096/fj.202401669R","DOIUrl":"https://doi.org/10.1096/fj.202401669R","url":null,"abstract":"<p>Intestinal microbes can beneficially impact host physiology, prompting investigations into the therapeutic usage of such microbes in a range of diseases. For example, human intestinal microbe <i>Limosilactobacillus reuteri</i> strains ATCC PTA 6475 and DSM 17938 are being considered for use for intestinal ailments, including colic, infection, and inflammation, as well as for non-intestinal ailments, including osteoporosis, wound healing, and autism spectrum disorder. While many of their beneficial properties are attributed to suppressing inflammatory responses, we postulated that <i>L. reuteri</i> may also regulate intestinal hormones to affect physiology within and outside of the gut. To determine if <i>L. reuteri</i> secreted factors impact the secretion of enteric hormones, we treated an engineered jejunal organoid line, <i>NGN3</i>-HIO, which can be induced to be enriched in enteroendocrine cells, with <i>L. reuteri</i> 6475 or 17938 conditioned medium and performed transcriptomics. Our data suggest that these <i>L. reuteri</i> strains affect the transcription of many gut hormones, including vasopressin and luteinizing hormone subunit beta, which have not been previously recognized as produced in the gut epithelium. Moreover, we find that these hormones appear to be produced in enterocytes, in contrast to canonical gut hormones produced in enteroendocrine cells. Finally, we show that <i>L. reuteri</i> conditioned media promote the secretion of enteric hormones, including serotonin, GIP, PYY, vasopressin, and luteinizing hormone subunit beta, and identify by metabolomics metabolites potentially mediating these effects on hormones. These results support <i>L. reuteri</i> affecting host physiology through intestinal hormone secretion, thereby expanding our understanding of the mechanistic actions of this microbe.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 6","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401669R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143638993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep-sea photodynamic vision at low light level — Which is more important, prosthetic retinal or apo-rhodopsin moiety?","authors":"Zong Jie Cui","doi":"10.1096/fj.202500213R","DOIUrl":"https://doi.org/10.1096/fj.202500213R","url":null,"abstract":"<p>The special case of far-red vision of mesopelagic dragonfish <i>Malacosteus niger</i> facilitated by the presence in the rod outer segment of photosensitizer chlorin e6 from diet has drawn considerable attention both in vision research and in photodynamic action. Rhodopsin binding of Ce6 from either the extracellular or intracellular loops may exert different effects. Theoretical works predict that the extracellularly bound Ce6 upon absorption of red light produces a singlet oxygen, which could via an oxygen tunnel reach the Lys-tethered 11-cis-retinal, by way of peroxy–dioxetane intermediates, to enhance 11-cis- to all-trans-retinal isomerization, therefore triggering the ultrafast phototransduction process. Recent works on the permanent photodynamic activation of some A-class G protein-coupled receptors suggest that the singlet oxygen generated by Ce6 photodynamic action might also oxidize the scotopsin moiety of rhodopsin, leading to direct oxidative rhodopsin activation. More attention needs to be paid to the latter respects of the far-red vision process of the deep-sea dragonfish, with potential translational values.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 6","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZUP1 is a key component of the MAVS complex and acts as a protector of host against viral invasion","authors":"Wenyan Hao,&nbsp;Mengfan Guo,&nbsp;Xin Ji,&nbsp;Xuyang Zhao,&nbsp;Minglu Zhu,&nbsp;Yan Jin,&nbsp;Guangxi Wang,&nbsp;Jiawen Feng,&nbsp;Dan Lu,&nbsp;Yuxin Yin","doi":"10.1096/fj.202401661RRR","DOIUrl":"https://doi.org/10.1096/fj.202401661RRR","url":null,"abstract":"<p>Zinc finger-containing ubiquitin peptidase 1 (ZUP1) is a protein characterized by four N-terminal zinc finger domains and a C-terminal deubiquitinase (DUB) domain. While it is associated with the DNA damage response, the role of ZUP1 in innate immunity remains unclear. Here, we identify ZUP1 as a crucial component of the mitochondrial antiviral signaling (MAVS) complex, essential for host antiviral defense. We show that viral infection significantly upregulates ZUP1 expression, and mice lacking ZUP1 exhibit impaired type I interferon (IFN) production and increased susceptibility to viral infection, as evidenced by higher mortality rates. This underscores the protective role of ZUP1 in host immunity. Mechanistically, ZUP1 binds to MAVS through its C-terminal domain independently of DUB activity. Instead, ZUP1 utilizes its zinc finger domains, particularly the third zinc finger, to directly bind viral RNA. This interaction enhances the association of ZUP1 with MAVS and promotes its aggregation on mitochondria during viral infection. ZUP1 also interacts with TBK1 and NEMO within the MAVS complex, facilitating IRF3 activation and type I IFN production. These findings establish ZUP1 as a zinc finger-containing regulator that amplifies MAVS-dependent antiviral immunity, linking viral RNA recognition to downstream signaling and highlighting potential targets for therapeutic intervention against viral infections.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 6","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}