{"database":"biostudies-literature","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":62,"searchCount":0},"additional":{"submitter":["Piperno GM"],"funding":["Telethon"],"pagination":["132857"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7526445"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["5(17)"],"pubmed_abstract":["Dysregulated sensing of self-nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type I IFNs by innate cells. Here we show that immune complexes of self-DNA and autoantibodies (DNA-ICs) contribute to elevated IFN levels via activation of the cGAS/STING pathway of cytosolic sensing. Mechanistically, lack of endosomal F-actin nucleation by WASp caused a delay in endolysosomal maturation and prolonged the transit time of ingested DNA-ICs. Stalling in maturation-defective organelles facilitated leakage of DNA-ICs into the cytosol, promoting activation of the TBK1/STING pathway. Genetic deletion of STING and STING and cGAS chemical inhibitors abolished IFN production and rescued systemic activation of IFN-stimulated genes in vivo. These data unveil the contribution of cytosolic self-nucleic acid sensing in WAS and underscore the importance of WASp-mediated endosomal actin remodeling in preventing innate activation."],"journal":["JCI insight"],"pubmed_title":["Wiskott-Aldrich syndrome protein restricts cGAS/STING activation by dsDNA immune complexes."],"pmcid":["PMC7526445"],"funding_grant_id":["GGP14281"],"pubmed_authors":["Ali H","Haecker H","Piperno GM","Liv N","Klumperman J","Amadio R","Benvenuti F","Silvestrelli G","Caronni N","Hanna RN","Cervantes-Luevano KE","Benaroch P","Naseem A","Graziano F","Colliva A"],"view_count":["62"],"additional_accession":[]},"is_claimable":false,"name":"Wiskott-Aldrich syndrome protein restricts cGAS/STING activation by dsDNA immune complexes.","description":"Dysregulated sensing of self-nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type I IFNs by innate cells. Here we show that immune complexes of self-DNA and autoantibodies (DNA-ICs) contribute to elevated IFN levels via activation of the cGAS/STING pathway of cytosolic sensing. Mechanistically, lack of endosomal F-actin nucleation by WASp caused a delay in endolysosomal maturation and prolonged the transit time of ingested DNA-ICs. Stalling in maturation-defective organelles facilitated leakage of DNA-ICs into the cytosol, promoting activation of the TBK1/STING pathway. Genetic deletion of STING and STING and cGAS chemical inhibitors abolished IFN production and rescued systemic activation of IFN-stimulated genes in vivo. These data unveil the contribution of cytosolic self-nucleic acid sensing in WAS and underscore the importance of WASp-mediated endosomal actin remodeling in preventing innate activation.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Sep","modification":"2024-02-15T10:48:54.4Z","creation":"2020-10-29T08:11:14Z"},"accession":"S-EPMC7526445","cross_references":{"pubmed":["32721945"],"doi":["10.1172/jci.insight.132857"]}}