2. Academic Validation
  3. Inflammasome Activation Triggers Caspase-1-Mediated Cleavage of cGAS to Regulate Responses to DNA Virus Infection

Inflammasome Activation Triggers Caspase-1-Mediated Cleavage of cGAS to Regulate Responses to DNA Virus Infection

  • Immunity. 2017 Mar 21;46(3):393-404. doi: 10.1016/j.immuni.2017.02.011.
Yutao Wang 1,  Xiaohan Ning 1,  Pengfei Gao 1,  Shuxian Wu 2,  Mengyin Sha 1,  Mengze Lv 1,  Xiang Zhou 1,  Juyi Gao 1,  Run Fang 1,  Guangxun Meng 2,  Xiaodong Su 3,  Zhengfan Jiang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; 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 Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
  • 3 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
  • 4 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; 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. Electronic address: jiangzf@pku.edu.cn.
PMID: 28314590 DOI: 10.1016/j.immuni.2017.02.011
Abstract

Viral Infection triggers host innate immune responses that result in the production of various cytokines including type I interferons (IFN), activation of inflammasomes, and programmed cell death of the infected cells. Tight control of inflammatory cytokine production is crucial for the triggering of an effective immune response that can resolve the Infection without causing host pathology. In examining the inflammatory response of Asc-/- and Casp1-/- macrophages, we found that deficiency in these molecules resulted in increased IFN production upon DNA virus Infection, but not RNA virus challenge. Investigation of the underlying mechanism revealed that upon canonical and non-canonical inflammasome activation, Caspase-1 interacted with cyclic GMP-AMP (cGAMP) synthase (cGAS), cleaving it and dampening cGAS-STING-mediated IFN production. Deficiency in inflammasome signaling enhanced host resistance to DNA virus in vitro and in vivo, and this regulatory role extended to other inflammatory caspases. Thus, inflammasome activation dampens cGAS-dependent signaling, suggesting cross-regulation between intracellular DNA-sensing pathways.

Keywords

Innate immunity; STING; cGAS; caspase-1; inflammasome; type I-interferons; viral infection.

Figures