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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\u2013nucleic acid sensing in WAS and underscore the importance of WASp-mediated endosomal actin remodeling in preventing innate activation.<\/jats:p>","DOI":"10.1172\/jci.insight.132857","type":"journal-article","created":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T13:41:18Z","timestamp":1595943678000},"source":"Crossref","is-referenced-by-count":14,"title":["Wiskott-Aldrich syndrome protein restricts cGAS\/STING activation by dsDNA immune complexes"],"prefix":"10.1172","volume":"5","author":[{"given":"Giulia Maria","family":"Piperno","sequence":"first","affiliation":[{"name":"International Centre for Genetic Engineering and Biotechnology, Trieste, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3612-2336","authenticated-orcid":true,"given":"Asma","family":"Naseem","sequence":"additional","affiliation":[{"name":"International Centre for Genetic Engineering and 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