Apoptotic Caspases Control Innate Immunity via the Cleavage of Key Proteins

Published: 7 February 2019| Version 3 | DOI: 10.17632/85kk99yf2v.3
Zhengfan Jiang


Viral infection triggers host defenses through pattern-recognition receptor-mediated cytokine production, inflammasome activation, and apoptosis of the infected cells. Inflammasome-activated caspases are known to cleave cyclic GMP-AMP synthase (cGAS). Here, we found that apoptotic caspases are critically involved in regulating both DNA and RNA virus-triggered host defenses, in which activated caspase-3 cleaved cGAS, MAVS and IRF3 to prevent cytokine overproduction. Caspase-3 was exclusively required in human cells, whereas caspase-7 was only involved in murine cells to inactivate cGAS, reflecting distinct regulatory mechanisms in different species. Caspase-mediated cGAS cleavage was enhanced in the presence of dsDNA. Interestingly, alternative MAVS cleavage sites were utilized to assure the inactivation of this critical protein. Elevated type I-IFNs were detected in caspase-3-deficient cells without any infection. Consistently, Casp3−⁄− mice showed increased resistance to viral infection and experimental autoimmune encephalomyelitis. Our results demonstrate that apoptotic caspases control innate immunity and maintain immune homeostasis against viral infection.



Viruses, Cytokines, Apoptosis, Caspase, Innate Immunity