Yang Li, Shachi P Vyas, Isha Mehta, Nariaki Asada, Ipsita Dey, Tiffany C Taylor, Rami Bechara, Nilesh Amatya, Felix E Y Aggor, Bianca M Coleman, De-Dong Li, Kenta Yamamoto, Ogechukwu Ezenwa, Yeque Sun, Esta Sterneck, C Joel McManus, Ulf Panzer, Partha S Biswas, Ram Savan, Jishnu Das, Sarah L Gaffen
{"title":"RNA结合蛋白Arid5a驱动IL-17依赖性自身抗体诱导的肾小球肾炎。","authors":"Yang Li, Shachi P Vyas, Isha Mehta, Nariaki Asada, Ipsita Dey, Tiffany C Taylor, Rami Bechara, Nilesh Amatya, Felix E Y Aggor, Bianca M Coleman, De-Dong Li, Kenta Yamamoto, Ogechukwu Ezenwa, Yeque Sun, Esta Sterneck, C Joel McManus, Ulf Panzer, Partha S Biswas, Ram Savan, Jishnu Das, Sarah L Gaffen","doi":"10.1084/jem.20240656","DOIUrl":null,"url":null,"abstract":"<p><p>Autoantibody-mediated glomerulonephritis (AGN) arises from dysregulated renal inflammation, with urgent need for improved treatments. IL-17 is implicated in AGN and drives pathology in a kidney-intrinsic manner via renal tubular epithelial cells (RTECs). Nonetheless, downstream signaling mechanisms provoking kidney pathology are poorly understood. A noncanonical RNA binding protein (RBP), Arid5a, was upregulated in human and mouse AGN. Arid5a-/- mice were refractory to AGN, with attenuated myeloid infiltration and impaired expression of IL-17-dependent cytokines and transcription factors (C/EBPβ, C/EBPδ). Transcriptome-wide RIP-Seq revealed that Arid5a inducibly interacts with conventional IL-17 target mRNAs, including CEBPB and CEBPD. Unexpectedly, many Arid5a RNA targets corresponded to translational regulation and RNA processing pathways, including rRNAs. Indeed, global protein synthesis was repressed in Arid5a-deficient cells, and C/EBPs were controlled at the level of protein rather than RNA accumulation. IL-17 prompted Arid5a nuclear export and association with 18S rRNA, a 40S ribosome constituent. Accordingly, IL-17-dependent renal autoimmunity is driven by Arid5a at the level of ribosome interactions and translation.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6000,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284280/pdf/","citationCount":"0","resultStr":"{\"title\":\"The RNA binding protein Arid5a drives IL-17-dependent autoantibody-induced glomerulonephritis.\",\"authors\":\"Yang Li, Shachi P Vyas, Isha Mehta, Nariaki Asada, Ipsita Dey, Tiffany C Taylor, Rami Bechara, Nilesh Amatya, Felix E Y Aggor, Bianca M Coleman, De-Dong Li, Kenta Yamamoto, Ogechukwu Ezenwa, Yeque Sun, Esta Sterneck, C Joel McManus, Ulf Panzer, Partha S Biswas, Ram Savan, Jishnu Das, Sarah L Gaffen\",\"doi\":\"10.1084/jem.20240656\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Autoantibody-mediated glomerulonephritis (AGN) arises from dysregulated renal inflammation, with urgent need for improved treatments. IL-17 is implicated in AGN and drives pathology in a kidney-intrinsic manner via renal tubular epithelial cells (RTECs). Nonetheless, downstream signaling mechanisms provoking kidney pathology are poorly understood. A noncanonical RNA binding protein (RBP), Arid5a, was upregulated in human and mouse AGN. Arid5a-/- mice were refractory to AGN, with attenuated myeloid infiltration and impaired expression of IL-17-dependent cytokines and transcription factors (C/EBPβ, C/EBPδ). Transcriptome-wide RIP-Seq revealed that Arid5a inducibly interacts with conventional IL-17 target mRNAs, including CEBPB and CEBPD. Unexpectedly, many Arid5a RNA targets corresponded to translational regulation and RNA processing pathways, including rRNAs. Indeed, global protein synthesis was repressed in Arid5a-deficient cells, and C/EBPs were controlled at the level of protein rather than RNA accumulation. IL-17 prompted Arid5a nuclear export and association with 18S rRNA, a 40S ribosome constituent. Accordingly, IL-17-dependent renal autoimmunity is driven by Arid5a at the level of ribosome interactions and translation.</p>\",\"PeriodicalId\":15760,\"journal\":{\"name\":\"Journal of Experimental Medicine\",\"volume\":\"221 9\",\"pages\":\"\"},\"PeriodicalIF\":12.6000,\"publicationDate\":\"2024-09-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284280/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Experimental Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1084/jem.20240656\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/26 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1084/jem.20240656","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/26 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
The RNA binding protein Arid5a drives IL-17-dependent autoantibody-induced glomerulonephritis.
Autoantibody-mediated glomerulonephritis (AGN) arises from dysregulated renal inflammation, with urgent need for improved treatments. IL-17 is implicated in AGN and drives pathology in a kidney-intrinsic manner via renal tubular epithelial cells (RTECs). Nonetheless, downstream signaling mechanisms provoking kidney pathology are poorly understood. A noncanonical RNA binding protein (RBP), Arid5a, was upregulated in human and mouse AGN. Arid5a-/- mice were refractory to AGN, with attenuated myeloid infiltration and impaired expression of IL-17-dependent cytokines and transcription factors (C/EBPβ, C/EBPδ). Transcriptome-wide RIP-Seq revealed that Arid5a inducibly interacts with conventional IL-17 target mRNAs, including CEBPB and CEBPD. Unexpectedly, many Arid5a RNA targets corresponded to translational regulation and RNA processing pathways, including rRNAs. Indeed, global protein synthesis was repressed in Arid5a-deficient cells, and C/EBPs were controlled at the level of protein rather than RNA accumulation. IL-17 prompted Arid5a nuclear export and association with 18S rRNA, a 40S ribosome constituent. Accordingly, IL-17-dependent renal autoimmunity is driven by Arid5a at the level of ribosome interactions and translation.
期刊介绍:
Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field.
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