Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis

Cell Host Microbe. 2015 Jun 10;17(6):820-8. doi: 10.1016/j.chom.2015.05.005. Epub 2015 Jun 2.

Abstract

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 mouse macrophages 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • DNA, Bacterial / metabolism*
  • DNA-Binding Proteins / metabolism
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Immunity, Innate
  • Interferon-beta / immunology
  • Interferon-beta / metabolism
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mycobacterium tuberculosis / genetics*
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism*
  • Proto-Oncogene Proteins c-ets / metabolism
  • Transcription Factors / metabolism
  • Tuberculosis / microbiology*
  • Tuberculosis / mortality

Substances

  • DNA, Bacterial
  • DNA-Binding Proteins
  • ELF3 protein, human
  • MPYS protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins c-ets
  • Transcription Factors
  • Interferon-beta
  • MB21D1 protein, human
  • Nucleotidyltransferases
  • cGAS protein, mouse