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CLPP-null mice exhibit growth retardation, deafness, and sterility, resembling human Perrault syndrome, but also display immune system alterations. However, the molecular mechanisms and signaling pathways underlying immunological changes in CLPP-null mice remain unclear. In this study, we report the steady-state activation of type I IFN signaling and antiviral gene expression in CLPP-deficient cells and tissues, resulting in marked resistance to RNA and DNA virus infection. Depletion of the cyclic GMP-AMP (cGAS)\u2013stimulator of IFN genes (STING) DNA sensing pathway reduces steady-state IFN-I signaling and abrogates the broad antiviral phenotype of CLPP-null cells. Moreover, we report that CLPP deficiency leads to mitochondrial DNA (mtDNA) instability and packaging alterations. Pharmacological and genetic approaches to deplete mtDNA or inhibit cytosolic release markedly reduce antiviral gene expression, implicating mtDNA stress as the driver of IFN-I signaling in CLPP-null mice. Our work places the cGAS\u2013STING\u2013IFN-I innate immune pathway downstream of CLPP and may have implications for understanding Perrault syndrome and other human diseases involving CLPP dysregulation.<\/jats:p>","DOI":"10.4049\/jimmunol.2001016","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T11:00:12Z","timestamp":1615978812000},"page":"1890-1900","source":"Crossref","is-referenced-by-count":57,"title":["Loss of Mitochondrial Protease CLPP Activates Type I IFN Responses through the Mitochondrial DNA\u2013cGAS\u2013STING Signaling Axis"],"prefix":"10.1093","volume":"206","author":[{"given":"Sylvia","family":"Torres-Odio","sequence":"first","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University Health Science Center , Bryan, TX 77807"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7486-4261","authenticated-orcid":false,"given":"Yuanjiu","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University Health Science Center , Bryan, TX 77807"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzana","family":"Gispert","sequence":"additional","affiliation":[{"name":"Experimental Neurology, Goethe University , 60590 Frankfurt am Main ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Maletzko","sequence":"additional","affiliation":[{"name":"Experimental Neurology, Goethe University , 60590 Frankfurt am Main ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Key","sequence":"additional","affiliation":[{"name":"Experimental Neurology, Goethe University , 60590 Frankfurt am Main ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeed S","family":"Menissy","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University Health Science Center , Bryan, TX 77807"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilka","family":"Wittig","sequence":"additional","affiliation":[{"name":"Functional Proteomics, Faculty of Medicine, Goethe University , 60590 Frankfurt am Main ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Auburger","sequence":"additional","affiliation":[{"name":"Experimental Neurology, Goethe University , 60590 Frankfurt am Main ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2884-6895","authenticated-orcid":false,"given":"A Phillip","family":"West","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University Health Science Center , Bryan, TX 77807"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"key":"2025030418555255100_r1","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nrm3984","article-title":"New roles for mitochondrial proteases in health, ageing and disease","volume":"16","author":"Quir\u00f3s","year":"2015","journal-title":"Nat. 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