title: Sumoylation Promotes the Stability of the DNA Sensor cGAS and the Adaptor STING to Regulate the Kinetics of Response to DNA Virus.
abstract: During viral infection, sensing of cytosolic DNA by the cyclic GMP-AMP synthase (cGAS) activates the adaptor protein STING and triggers an antiviral response. Little is known about the mechanisms that determine the kinetics of activation and deactivation of the cGAS-STING pathway, ensuring effective but controlled innate antiviral responses. Here we found that the ubiquitin ligase Trim38 targets cGas for sumoylation in uninfected cells and during the early phase of viral infection. Sumoylation of cGas prevented its polyubiquitination and degradation. Trim38 also sumoylated Sting during the early phase of viral infection, promoting both Sting activation and protein stability. In the late phase of infection, cGas and Sting were desumoylated by Senp2 and subsequently degraded via proteasomal and chaperone-mediated autophagy pathways, respectively. Our findings reveal an essential role for Trim38 in the innate immune response to DNA virus and provide insight into the mechanisms that ensure optimal activation and deactivation of the cGAS-STING pathway.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China, 430072; Medical Research Institute, Wuhan University, Wuhan, China, 430072.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Hu
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China, 430072; Medical Research Institute, Wuhan University, Wuhan, China, 430072.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Medical Research Institute, Wuhan University, Wuhan, China, 430072.
authors.forename: Xue-Qin
authors.initials: XQ
authors.lastname: Xie
authors.affiliation: Medical Research Institute, Wuhan University, Wuhan, China, 430072.
authors.forename: Chen-Yang
authors.initials: CY
authors.lastname: Liao
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China, 430072.
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China, 430072; Medical Research Institute, Wuhan University, Wuhan, China, 430072.
authors.forename: Tian-Tian
authors.initials: TT
authors.lastname: Liu
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China, 430072.
authors.forename: Lei
authors.initials: L
authors.lastname: Yin
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China, 430072; Medical Research Institute, Wuhan University, Wuhan, China, 430072; Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan, China, 430072. Electronic address: shuh@whu.edu.cn.
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004267:DNA Viruses / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology; D058207:Sumoylation / Q000276:immunology / Q000502:physiology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000276:immunology / Q000502:physiology; D014777:Virus Diseases / Q000378:metabolism*; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D002352:Carrier Proteins; D003546:Cysteine Endopeptidases; D004247:DNA; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D046988:Proteasome Endopeptidase Complex; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; C530855:Sting1 protein, mouse; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C574194:TRIM38 protein, mouse; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase