2. Academic Validation
  3. Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3

Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3

  • Mol Cell. 2019 Apr 4;74(1):19-31.e7. doi: 10.1016/j.molcel.2019.02.013.
Xiaohan Ning 1,  Yutao Wang 1,  Miao Jing 1,  Mengyin Sha 1,  Mengze Lv 1,  Pengfei Gao 1,  Rui Zhang 1,  Xiaojun Huang 2,  Ji-Ming Feng 3,  Zhengfan Jiang 4
Affiliations

Affiliations

  • 1 Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Beijing 100871, China.
  • 2 Peking-Tsinghua Center for Life Sciences, Beijing 100871, China; Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Beijing 100044, China.
  • 3 Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
  • 4 Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Beijing 100871, China; Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Beijing 100044, China. Electronic address: [email protected].
PMID: 30878284 DOI: 10.1016/j.molcel.2019.02.013
Abstract

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 involved only in murine cells to inactivate cGAS, reflecting distinct regulatory mechanisms in different species. Caspase-mediated cGAS cleavage was enhanced in the presence of dsDNA. Alternative MAVS cleavage sites were used to ensure the inactivation of this critical protein. Elevated type I IFNs were detected in caspase-3-deficient cells without any Infection. Casp3-/- mice consistently 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.

Keywords

IRF3; MAVS; apoptosis; apoptotic caspase; cGAS; cleavage; immunologically silent; innate immunity; type I-interferon; virus infection.

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