Pub Date : 2025-09-10DOI: 10.1038/s41423-025-01335-1
Derk Amsen
{"title":"Restoration of the peace in autoimmune disease: tired of fighting?","authors":"Derk Amsen","doi":"10.1038/s41423-025-01335-1","DOIUrl":"10.1038/s41423-025-01335-1","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 10","pages":"1276-1278"},"PeriodicalIF":19.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Upon DNA virus infection, cGAS senses viral DNA and triggers MITA (also called STING)-dependent induction of type I interferons (IFN-Is) and other cytokines/chemokines. IFN-Is further activate STAT1/2 to induce interferon-stimulated genes (ISGs) and the innate antiviral response. How the innate antiviral response is silenced in uninfected cells and efficiently mounts upon viral infection is not fully understood. In this study, we found that FBXW7, a substrate recognition component of the SCF E3 ubiquitin ligase complex, is a multifaceted regulator of the innate immune response to DNA viruses. In uninfected cells, FBXW7 mediates the polyubiquitination and degradation of GSK3α/β-phosphorylated SLC35B2/3 at the Golgi apparatus. This leads to the downregulation of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus and the inactivation of MITA in uninfected cells. In addition, FBXW7 mediates the degradation of GSK3α/β-phosphorylated MYC, which is a repressor of STAT1/2, leading to proper STAT1/2 levels in uninfected cells. The differential regulation of FBXW7 on MITA and STAT1/2 ensures inactivation but is ready for fast mount of the innate immune response in uninfected cells. Infection with DNA viruses activates the PI3K‒AKT axis, which inactivates GSK3α/β and inhibits FBXW7-mediated polyubiquitination and degradation of SLC35B2/3, leading to increased production of sGAGs, activation of MITA and rapid onset of the innate antiviral response. Consistently, gene disruption experiments indicate that FBXW7 modulates the innate antiviral response in human THP-1 and mouse BMDM cells. These findings suggest that FBXW7 functions as a versatile regulator of the innate immune response to DNA viruses by differentially regulating upstream and downstream components of the type I interferon induction loop.
{"title":"FBXW7 is a multifaceted regulator of the innate immune response to DNA viruses","authors":"Xue-Dan Sun, Jia-Li Wang, Xin-Yu Zhang, Zi-Lun Ruan, Wei Liang, Yi Guo, Wei-Tao Guan, Qing Yang, Ling Li, Hong-Bing Shu, Ming-Ming Hu","doi":"10.1038/s41423-025-01336-0","DOIUrl":"10.1038/s41423-025-01336-0","url":null,"abstract":"Upon DNA virus infection, cGAS senses viral DNA and triggers MITA (also called STING)-dependent induction of type I interferons (IFN-Is) and other cytokines/chemokines. IFN-Is further activate STAT1/2 to induce interferon-stimulated genes (ISGs) and the innate antiviral response. How the innate antiviral response is silenced in uninfected cells and efficiently mounts upon viral infection is not fully understood. In this study, we found that FBXW7, a substrate recognition component of the SCF E3 ubiquitin ligase complex, is a multifaceted regulator of the innate immune response to DNA viruses. In uninfected cells, FBXW7 mediates the polyubiquitination and degradation of GSK3α/β-phosphorylated SLC35B2/3 at the Golgi apparatus. This leads to the downregulation of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus and the inactivation of MITA in uninfected cells. In addition, FBXW7 mediates the degradation of GSK3α/β-phosphorylated MYC, which is a repressor of STAT1/2, leading to proper STAT1/2 levels in uninfected cells. The differential regulation of FBXW7 on MITA and STAT1/2 ensures inactivation but is ready for fast mount of the innate immune response in uninfected cells. Infection with DNA viruses activates the PI3K‒AKT axis, which inactivates GSK3α/β and inhibits FBXW7-mediated polyubiquitination and degradation of SLC35B2/3, leading to increased production of sGAGs, activation of MITA and rapid onset of the innate antiviral response. Consistently, gene disruption experiments indicate that FBXW7 modulates the innate antiviral response in human THP-1 and mouse BMDM cells. These findings suggest that FBXW7 functions as a versatile regulator of the innate immune response to DNA viruses by differentially regulating upstream and downstream components of the type I interferon induction loop.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 11","pages":"1427-1443"},"PeriodicalIF":19.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-08DOI: 10.1038/s41423-025-01344-0
Le-xi Wu, Jia-huan Xie, Jie-yu Li, Wen-ping Li, Xin-tao Mao, Ling-jie Huang, Hao-tian Chen, Jiang-yan Zhong, Li-min Lin, Shicheng Su, Yi-yuan Li, Qian Cao, Jin Jin
Anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD) is hampered by issues of nonresponse and resistance, highlighting the urgent need for alternative or complementary treatments. Our study revealed significant upregulation of taurine in the intestinal tissues of IBD patients, which was inversely related to the severity of the disease. A key discovery was that TNF directly induced taurine synthesis in intestinal epithelial cells and increased the production of angiogenin, a nuclease that degrades mitochondrial RNA, which is known to amplify inflammatory responses. By degrading mitochondrial RNA, angiogenin inhibits the inflammatory response in macrophages, suggesting a potent immune-modulatory role for taurine. This mechanism implies that taurine could serve as an adjunct to anti-TNF therapies, enhancing their efficacy and providing a novel strategy for the management of IBD and other chronic inflammatory diseases by harnessing the body’s innate immune regulatory mechanisms.
{"title":"Intestinal taurine acts as a novel immunometabolic modulator of IBD by degrading redundant mitochondrial RNA","authors":"Le-xi Wu, Jia-huan Xie, Jie-yu Li, Wen-ping Li, Xin-tao Mao, Ling-jie Huang, Hao-tian Chen, Jiang-yan Zhong, Li-min Lin, Shicheng Su, Yi-yuan Li, Qian Cao, Jin Jin","doi":"10.1038/s41423-025-01344-0","DOIUrl":"10.1038/s41423-025-01344-0","url":null,"abstract":"Anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD) is hampered by issues of nonresponse and resistance, highlighting the urgent need for alternative or complementary treatments. Our study revealed significant upregulation of taurine in the intestinal tissues of IBD patients, which was inversely related to the severity of the disease. A key discovery was that TNF directly induced taurine synthesis in intestinal epithelial cells and increased the production of angiogenin, a nuclease that degrades mitochondrial RNA, which is known to amplify inflammatory responses. By degrading mitochondrial RNA, angiogenin inhibits the inflammatory response in macrophages, suggesting a potent immune-modulatory role for taurine. This mechanism implies that taurine could serve as an adjunct to anti-TNF therapies, enhancing their efficacy and providing a novel strategy for the management of IBD and other chronic inflammatory diseases by harnessing the body’s innate immune regulatory mechanisms.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 11","pages":"1398-1413"},"PeriodicalIF":19.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gut-derived metabolites are essential for liver fibrogenesis. The aim of this study was to determine the alteration of indole-3-propionic acid (IPA), a crucial tryptophan metabolite, in liver fibrosis and delineate the roles of enterogenic IPA in fibrogenesis. In the present study, metabolomics assays focused on tryptophan metabolism were applied to explore the decreased levels of IPA in the feces and serum of cirrhotic patients, as well as in the feces and portal vein serum of fibrotic mice. Oral IPA administration exerted strong antifibrotic effects with favorable biosafety in three fibrotic models via multicellular modulation. Multiplex immunohistochemical staining and DAOSLIMIT imaging demonstrated that gut-derived IPA was directly captured by hepatic macrophages. Macrophage-specific AhR knockout blocked the antifibrotic effect of IPA, while the therapeutic efficacy was maintained in mice with HSC- or hepatocyte-specific AhR depletion. Furthermore, IPA governed macrophage recruitment, S100A8/A9+ phenotype transformation and profibrotic and proinflammatory functions, resulting in amelioration of hepatic fibrogenesis. Mechanistically, IPA targeted the AhR/NF-κB/S100A8/A9 axis and AhR/SPHK2/S1P signaling to inhibit the profibrotic biological characteristics of macrophages and subsequently interrupted the profibrogenic crosstalk between macrophages and hepatic stellate cells (HSCs) in coculture systems and 3D liver spheroid models. These findings increase the understanding of the effects of enterogenic tryptophan metabolites on liver fibrogenesis via the gut‒liver axis and support the translational potential of IPA. By targeting profibrogenic macrophages, IPA could serve as a promising candidate for the clinical management of liver fibrosis.
{"title":"Gut-derived indole propionic acid alleviates liver fibrosis by targeting profibrogenic macrophages via the gut‒liver axis","authors":"Yuanyuan Luo, Yarong Hao, Chunyan Sun, Zhi Lu, Hao Wang, Yuhan Lin, Yaping Guan, Lingyan Cai, Chenhong Ding, Binbin Li, Fei Chen, Yiting Lu, Yong Lin, Xin Zeng","doi":"10.1038/s41423-025-01339-x","DOIUrl":"10.1038/s41423-025-01339-x","url":null,"abstract":"Gut-derived metabolites are essential for liver fibrogenesis. The aim of this study was to determine the alteration of indole-3-propionic acid (IPA), a crucial tryptophan metabolite, in liver fibrosis and delineate the roles of enterogenic IPA in fibrogenesis. In the present study, metabolomics assays focused on tryptophan metabolism were applied to explore the decreased levels of IPA in the feces and serum of cirrhotic patients, as well as in the feces and portal vein serum of fibrotic mice. Oral IPA administration exerted strong antifibrotic effects with favorable biosafety in three fibrotic models via multicellular modulation. Multiplex immunohistochemical staining and DAOSLIMIT imaging demonstrated that gut-derived IPA was directly captured by hepatic macrophages. Macrophage-specific AhR knockout blocked the antifibrotic effect of IPA, while the therapeutic efficacy was maintained in mice with HSC- or hepatocyte-specific AhR depletion. Furthermore, IPA governed macrophage recruitment, S100A8/A9+ phenotype transformation and profibrotic and proinflammatory functions, resulting in amelioration of hepatic fibrogenesis. Mechanistically, IPA targeted the AhR/NF-κB/S100A8/A9 axis and AhR/SPHK2/S1P signaling to inhibit the profibrotic biological characteristics of macrophages and subsequently interrupted the profibrogenic crosstalk between macrophages and hepatic stellate cells (HSCs) in coculture systems and 3D liver spheroid models. These findings increase the understanding of the effects of enterogenic tryptophan metabolites on liver fibrogenesis via the gut‒liver axis and support the translational potential of IPA. By targeting profibrogenic macrophages, IPA could serve as a promising candidate for the clinical management of liver fibrosis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 11","pages":"1414-1426"},"PeriodicalIF":19.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Disruption of the intestinal epithelial barrier and incomplete repair are critical for the development of colitis. V-domain immunoglobulin domain suppressor of T-cell activation (VISTA), encoded by Vsir, functions as an immune checkpoint. In the present work, we report that VISTA is predominantly upregulated in macrophages from patients with inflammatory bowel disease (IBD) and in mice with dextran sulfate sodium (DSS)-induced colitis. VISTA deficiency or blockade ameliorates DSS-induced colitis severity. Epithelial damage is notably less severe in Vsir−/−Rag1−/− mice than in Vsir+/+Rag1−/− mice. Intriguingly, macrophage depletion eliminates disease severity differences between Vsir−/− and wild-type (WT) mice. Vsir ablation does not alter cytokine profiles or macrophage differentiation but alleviates macrophage-mediated epithelial injury, as Vsir−/− macrophage transfer induces milder damage than WT macrophage transfer does. Interestingly, Vsir−/− mice exhibit accelerated mucosal regeneration during acute colitis. Mechanistically, macrophage-derived VISTA interacts with leucine-rich repeats and immunoglobulin-like domain 1 (LRIG1) in intestinal stem cells and suppresses peroxisome proliferator-activated receptor alpha (PPARα), leading to impeded growth of intestinal organoids and increased epithelial damage in mice with DSS-induced colitis. These findings reveal a pathogenic function of macrophage-derived VISTA in epithelial damage during colitis. Targeting the VISTA/LRIG1 axis could promote epithelial repair and serve as a promising therapeutic strategy for patients with IBD.
{"title":"Macrophage-derived VISTA engages with LRIG1 and hinders gut epithelial repair in colitis","authors":"Mengyuan Li, Binfeng Chen, Zhixiong Wang, Ruixiang Guo, Ningjing Xiong, Yichao Qian, Baokui Ye, Yimei Lai, Shuyi Wang, Yijun Zhu, Niansheng Yang, Hui Zhang","doi":"10.1038/s41423-025-01338-y","DOIUrl":"10.1038/s41423-025-01338-y","url":null,"abstract":"Disruption of the intestinal epithelial barrier and incomplete repair are critical for the development of colitis. V-domain immunoglobulin domain suppressor of T-cell activation (VISTA), encoded by Vsir, functions as an immune checkpoint. In the present work, we report that VISTA is predominantly upregulated in macrophages from patients with inflammatory bowel disease (IBD) and in mice with dextran sulfate sodium (DSS)-induced colitis. VISTA deficiency or blockade ameliorates DSS-induced colitis severity. Epithelial damage is notably less severe in Vsir−/−Rag1−/− mice than in Vsir+/+Rag1−/− mice. Intriguingly, macrophage depletion eliminates disease severity differences between Vsir−/− and wild-type (WT) mice. Vsir ablation does not alter cytokine profiles or macrophage differentiation but alleviates macrophage-mediated epithelial injury, as Vsir−/− macrophage transfer induces milder damage than WT macrophage transfer does. Interestingly, Vsir−/− mice exhibit accelerated mucosal regeneration during acute colitis. Mechanistically, macrophage-derived VISTA interacts with leucine-rich repeats and immunoglobulin-like domain 1 (LRIG1) in intestinal stem cells and suppresses peroxisome proliferator-activated receptor alpha (PPARα), leading to impeded growth of intestinal organoids and increased epithelial damage in mice with DSS-induced colitis. These findings reveal a pathogenic function of macrophage-derived VISTA in epithelial damage during colitis. Targeting the VISTA/LRIG1 axis could promote epithelial repair and serve as a promising therapeutic strategy for patients with IBD.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 11","pages":"1379-1397"},"PeriodicalIF":19.8,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-29DOI: 10.1038/s41423-025-01337-z
Douglas G. Burrin, Greg Guthrie, Caitlin Vonderohe
{"title":"Functional importance of bile acid-FXR signaling in neonatal immunity and disease","authors":"Douglas G. Burrin, Greg Guthrie, Caitlin Vonderohe","doi":"10.1038/s41423-025-01337-z","DOIUrl":"10.1038/s41423-025-01337-z","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 10","pages":"1279-1281"},"PeriodicalIF":19.8,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01337-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T-cell metabolism plays a pivotal role in defining T-cell functional states. Through analysis of a comprehensive pancancer single-cell transcriptional atlas, we identified SARDH, an enzyme involved in one-carbon (1-C) metabolism, as a potential T-cell metabolic checkpoint. SARDH significantly impacts T-cell fate and function, leading to impaired tumor control efficacy. Knocking down SARDH resulted in sarcosine accumulation and reduced consumption of S-adenosylmethionine (SAM), a critical methyl donor for epigenetic modulation, likely due to the shift in glycine-to-sarcosine homeostasis. Deletion of SARDH increased H3K79me2 modification at NF-κB-activating genes, thereby augmenting NF-κB signaling and T-cell function. Additionally, we observed transcriptional dysregulation of 1-C metabolism within tumors across various cancer types, which was often accompanied by increased sarcosine levels. Sarcosine was found to induce SARDH upregulation, suggesting a feedback mechanism for metabolic homeostasis in T cells within tumors. These findings underscore the potential effects and mechanism of targeting 1-C metabolism, particularly SARDH, as an avenue for cancer therapy.
{"title":"SARDH in the 1-C metabolism sculpts the T-cell fate and serves as a potential cancer therapeutic target","authors":"Wen Si, Sijin Cheng, Haiyin He, Yu Zhang, Yuhui Miao, Dingcheng Yi, Mengjiao Ni, Anqiang Wang, Hongtao Fan, Yufei Bo, Chang Liu, Zhaode Bu, Linnan Zhu, Zemin Zhang","doi":"10.1038/s41423-025-01331-5","DOIUrl":"10.1038/s41423-025-01331-5","url":null,"abstract":"T-cell metabolism plays a pivotal role in defining T-cell functional states. Through analysis of a comprehensive pancancer single-cell transcriptional atlas, we identified SARDH, an enzyme involved in one-carbon (1-C) metabolism, as a potential T-cell metabolic checkpoint. SARDH significantly impacts T-cell fate and function, leading to impaired tumor control efficacy. Knocking down SARDH resulted in sarcosine accumulation and reduced consumption of S-adenosylmethionine (SAM), a critical methyl donor for epigenetic modulation, likely due to the shift in glycine-to-sarcosine homeostasis. Deletion of SARDH increased H3K79me2 modification at NF-κB-activating genes, thereby augmenting NF-κB signaling and T-cell function. Additionally, we observed transcriptional dysregulation of 1-C metabolism within tumors across various cancer types, which was often accompanied by increased sarcosine levels. Sarcosine was found to induce SARDH upregulation, suggesting a feedback mechanism for metabolic homeostasis in T cells within tumors. These findings underscore the potential effects and mechanism of targeting 1-C metabolism, particularly SARDH, as an avenue for cancer therapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 11","pages":"1363-1378"},"PeriodicalIF":19.8,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01331-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-15DOI: 10.1038/s41423-025-01334-2
Qi Zhang, Zhen-Wu Ma, Hui-Fang Li, Jia-Qing Zeng, Hong-Bing Shu, Shu Li
T-cell immunoglobulin mucin family member-1 (TIM-1, also known as HAVCR1/KIM-1) is a transmembrane glycoprotein that has been reported to act as an entry receptor for multiple flaviviruses including Zika virus (ZIKV). The post-translational regulation of TIM-1 and its effects on ZIKV infection are unclear. In this study, we identified the membrane-associated RING-CH-type finger (MARCH) E3 ubiquitin ligase family members MARCH2 and MARCH3 as critical negative regulators of TIM-1 under physiological conditions. MARCH2 and MARCH3 associate with TIM-1 and mediate its K48-linked polyubiquitination at K338 and K346 respectively, leading to subsequent proteasomal degradation. While deficiency of either MARCH2 or MARCH3 modestly increases TIM-1 levels and enhances ZIKV infectivity, double knockout of MARCH2/3 has a more dramatic effect. Double knockout of MARCH2/3 increased ZIKV infectivity in wild-type but not TIM-1 knockout cells, and reconstitution of TIM-1K338R/K346R into TIM-1-deficient cells increases ZIKV infectivity to a higher degree than reconstitution with wild-type TIM-1. Knockout of either MARCH2 or MARCH3 increased ZIKV infectivity and pathogenesis in mice, whereas double knockout of MARCH2/3 has a more dramatic effect. These findings suggest that MARCH2 and MARCH3 target TIM-1 for K48-linked polyubiquitination and proteasomal degradation, thereby acting as redundant host restriction factors to limit ZIKV infection and pathogenesis.
{"title":"The membrane-associated ubiquitin ligases MARCH2 and MARCH3 target TIM-1 to limit Zika virus infection","authors":"Qi Zhang, Zhen-Wu Ma, Hui-Fang Li, Jia-Qing Zeng, Hong-Bing Shu, Shu Li","doi":"10.1038/s41423-025-01334-2","DOIUrl":"10.1038/s41423-025-01334-2","url":null,"abstract":"T-cell immunoglobulin mucin family member-1 (TIM-1, also known as HAVCR1/KIM-1) is a transmembrane glycoprotein that has been reported to act as an entry receptor for multiple flaviviruses including Zika virus (ZIKV). The post-translational regulation of TIM-1 and its effects on ZIKV infection are unclear. In this study, we identified the membrane-associated RING-CH-type finger (MARCH) E3 ubiquitin ligase family members MARCH2 and MARCH3 as critical negative regulators of TIM-1 under physiological conditions. MARCH2 and MARCH3 associate with TIM-1 and mediate its K48-linked polyubiquitination at K338 and K346 respectively, leading to subsequent proteasomal degradation. While deficiency of either MARCH2 or MARCH3 modestly increases TIM-1 levels and enhances ZIKV infectivity, double knockout of MARCH2/3 has a more dramatic effect. Double knockout of MARCH2/3 increased ZIKV infectivity in wild-type but not TIM-1 knockout cells, and reconstitution of TIM-1K338R/K346R into TIM-1-deficient cells increases ZIKV infectivity to a higher degree than reconstitution with wild-type TIM-1. Knockout of either MARCH2 or MARCH3 increased ZIKV infectivity and pathogenesis in mice, whereas double knockout of MARCH2/3 has a more dramatic effect. These findings suggest that MARCH2 and MARCH3 target TIM-1 for K48-linked polyubiquitination and proteasomal degradation, thereby acting as redundant host restriction factors to limit ZIKV infection and pathogenesis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 9","pages":"1032-1044"},"PeriodicalIF":19.8,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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