USP18 recruits USP20 to promote innate antiviral response through deubiquitinating STING/MITA

Cell Res. 2016 Dec;26(12):1302-1319. doi: 10.1038/cr.2016.125. Epub 2016 Nov 1.


STING (also known as MITA) mediates the innate antiviral signaling and ubiquitination of STING is key to its function. However, the deubiquitination process of STING is unclear. Here we report that USP18 recruits USP20 to deconjugate K48-linked ubiquitination chains from STING and promotes the stability of STING and the expression of type I IFNs and proinflammatory cytokines after DNA virus infection. USP18 deficiency or knockdown of USP20 resulted in enhanced K48-linked ubiquitination and accelerated degradation of STING, and impaired activation of IRF3 and NF-κB as well as induction of downstream genes after infection with DNA virus HSV-1 or transfection of various DNA ligands. In addition, Usp18-/- mice were more susceptible to HSV-1 infection compared with the wild-type littermates. USP18 did not deubiquitinate STING in vitro but facilitated USP20 to catalyze deubiquitination of STING in a manner independent of the enzymatic activity of USP18. In addition, reconstitution of STING into Usp18-/- MEFs restored HSV-1-induced expression of downstream genes and cellular antiviral responses. Our findings thus uncover previously uncharacterized roles of USP18 and USP20 in mediating virus-triggered signaling and contribute to the understanding of the complicated regulatory system of the innate antiviral responses.

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Cells, Cultured
  • Cytokines / antagonists & inhibitors
  • Cytokines / genetics
  • Cytokines / metabolism
  • Endopeptidases / chemistry
  • Endopeptidases / genetics
  • Endopeptidases / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Fibroblasts / virology
  • HEK293 Cells
  • Herpes Simplex / mortality
  • Herpes Simplex / pathology
  • Herpes Simplex / veterinary
  • Herpesvirus 1, Human / physiology
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Receptor, Interferon alpha-beta / deficiency
  • Receptor, Interferon alpha-beta / genetics
  • Signal Transduction
  • Survival Rate
  • Ubiquitin Thiolesterase / antagonists & inhibitors
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitins / antagonists & inhibitors
  • Ubiquitins / genetics
  • Ubiquitins / metabolism


  • Cytokines
  • G1p2 protein, mouse
  • Ifnar1 protein, mouse
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • MPYS protein, mouse
  • Membrane Proteins
  • NF-kappa B
  • Ubiquitins
  • Receptor, Interferon alpha-beta
  • Endopeptidases
  • Usp18 protein, mouse
  • Ubiquitin Thiolesterase
  • Usp20 protein, mouse