title: Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis.
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.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Collins
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
authors.forename: Haocheng
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
authors.forename: Tuo
authors.initials: T
authors.lastname: Li
authors.affiliation: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA.
authors.forename: Luis H
authors.initials: LH
authors.lastname: Franco
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA.
authors.forename: Vidhya R
authors.initials: VR
authors.lastname: Nair
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA.
authors.forename: Caitlyn R
authors.initials: CR
authors.lastname: Scharn
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA.
authors.forename: Chelsea E
authors.initials: CE
authors.lastname: Stamm
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Electronic address: zhijian.chen@utsouthwestern.edu.
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA. Electronic address: michael.shiloh@utsouthwestern.edu.
authors.forename: Michael U
authors.initials: MU
authors.lastname: Shiloh
mesh_terms: D000818:Animals; D001343:Autophagy; D004269:DNA, Bacterial / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014376:Tuberculosis / Q000382:microbiology* / Q000401:mortality; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D016899:Interferon-beta; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; C105529:ELF3 protein, human; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C578391:cGAS protein, mouse