Activation of the DNA-dependent cytosolic surveillance pathway in response to Mycobacterium tuberculosis infection stimulates ubiquitin-dependent autophagy and inflammatory cytokine production, and plays an important role in host defense against M.tuberculosis. However, the identity of the host sensor for M.tuberculosis DNA is unknown. Here we show that M.tuberculosis activated cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) in macrophages to produce cGAMP, a second messenger that activates the adaptor protein stimulator of interferon genes (STING) to induce type I interferons and other cytokines. cGAS localized with M.tuberculosis in mouse and human cells and in human tuberculosis lesions. Knockdown or knockout of cGAS in human or mousemacrophages blocked cytokine production and induction of autophagy. Mice deficient in cGAS were more susceptible to lethality caused by infection with M.tuberculosis. These results demonstrate that cGAS is a vital innate immune sensor of M.tuberculosis infection. Mycobacterium tuberculosis can activate the DNA-sensing cytosolic surveillance pathway. Collins etal. report that the recently discovered cyclic GMP-AMP synthase (cGAS) is the key innate sensor of M.tuberculosis DNA that has dual roles in inducing type I interferon and activating autophagy within mouse and human macrophages.
ASJC Scopus subject areas
- Immunology and Microbiology(all)
- Cancer Research
- Molecular Biology