Sumoylation Promotes the Stability of the DNA Sensor cGAS and the Adaptor STING to Regulate the Kinetics of Response to DNA Virus

Immunity. 2016 Sep 20;45(3):555-569. doi: 10.1016/j.immuni.2016.08.014. Epub 2016 Sep 13.


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.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cysteine Endopeptidases / metabolism
  • DNA / metabolism*
  • DNA Viruses / immunology*
  • Immunity, Innate / immunology
  • Kinetics
  • Membrane Proteins / metabolism
  • Mice
  • Nucleotides, Cyclic / metabolism*
  • Nucleotidyltransferases / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Signal Transduction / immunology
  • Signal Transduction / physiology
  • Sumoylation / immunology
  • Sumoylation / physiology*
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases
  • Ubiquitination / immunology
  • Ubiquitination / physiology
  • Virus Diseases / metabolism*


  • Carrier Proteins
  • Membrane Proteins
  • Nucleotides, Cyclic
  • Sting1 protein, mouse
  • Tripartite Motif Proteins
  • cyclic guanosine monophosphate-adenosine monophosphate
  • DNA
  • TRIM38 protein, mouse
  • Ubiquitin-Protein Ligases
  • Nucleotidyltransferases
  • cGAS protein, mouse
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex