Loss of Mitochondrial Protease CLPP Activates Type I IFN Responses through the Mitochondrial DNAcGASSTING Signaling Axis Academic Article uri icon


  • Abstract 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 (PS). Absence of CLPP also leads to immune system alterations but the molecular mechanisms and underlying signaling pathways 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 phenotype of CLPP-null cells. We report that CLPP deficiency leads to mitochondrial DNA (mtDNA) instability and packaging alterations, a phenotype also observed in CLPP mutant fibroblasts from PS patient. Our work places the cGAS-STING-IFN-I innate immune pathway downstream of CLPP and may have implications for understanding PS and other human diseases involving CLPP dysregulation and proteostasis. Office of the Assistant Secretary of Defense for Health Affairs, U.S. Department of Defense (W81XWH-17-1-0052; W81XWH-20-1-0150); National Heart, Lung, and Blood Institute, National Institutes of Health (R01HL148153)

published proceedings

  • The Journal of Immunology

author list (cited authors)

  • Torres-Odio, S., Lei, Y., Gispert, S., Maletzko, A., Key, J., Menissy, S., ... West, A. P.

citation count

  • 0

complete list of authors

  • Torres-Odio, Sylvia||Lei, Yuanjiu||Gispert, Suzana||Maletzko, Antonia||Key, Jana||Menissy, Saeed||Wittig, Ilka||Auburger, Georg||West, A Phillip

publication date

  • May 2022