biostudies-literatureTorres-Odio SNHLBI NIH HHSOffice of the Assistant Secretary of Defense for Health Affairs, U.S. Department of DefenseNational Heart, Lung, and Blood Institute, National Institutes of Health1890-1900https://www.ebi.ac.uk/biostudies/studies/S-EPMC8026707biostudies-literatureUnknown206(8)Caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) is a serine protease that degrades damaged or misfolded mitochondrial proteins. 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)-stimulator of IFN genes (STING) DNA sensing pathway reduces steady-state IFN-I signaling and abrogates the broad antiviral phenotypJournal of immunology (Baltimore, Md. : 1950)Loss of Mitochondrial Protease CLPP Activates Type I IFN Responses through the Mitochondrial DNA-cGAS-STING Signaling Axis.PMC8026707R01HL148153W81XWH-20-1-0150W81XWH-17-1-0052R01 HL148153West APTorres-Odio SWittig IMenissy SSLei YKey JAuburger GGispert SMaletzko AfalseLoss of Mitochondrial Protease CLPP Activates Type I IFN Responses through the Mitochondrial DNA-cGAS-STING Signaling Axis.Caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) is a serine protease that degrades damaged or misfolded mitochondrial proteins. 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)-stimulator of IFN genes (STING) DNA sensing pathway reduces steady-state IFN-I signaling and abrogates the broad antiviral phenotyp2021-01-01T00:00:00Z2021 Apr2026-05-09T20:09:57.839Z2025-02-19T00:56:26.682ZS-EPMC80267073373133810.4049/jimmunol.2001016