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USP18 recruits USP20 to promote innate antiviral response through deubiquitinating STING/MITA.
- Source :
-
Cell research [Cell Res] 2016 Dec; Vol. 26 (12), pp. 1302-1319. Date of Electronic Publication: 2016 Nov 01. - Publication Year :
- 2016
-
Abstract
- 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 <superscript>-/-</superscript> 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 <superscript>-/-</superscript> 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.
- Subjects :
- Animals
Bone Marrow Cells cytology
Bone Marrow Cells metabolism
Cells, Cultured
Cytokines antagonists & inhibitors
Cytokines genetics
Cytokines metabolism
Endopeptidases chemistry
Endopeptidases genetics
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
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
Ubiquitins antagonists & inhibitors
Ubiquitins genetics
Ubiquitins metabolism
Endopeptidases metabolism
Membrane Proteins metabolism
Ubiquitin Thiolesterase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1748-7838
- Volume :
- 26
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Cell research
- Publication Type :
- Academic Journal
- Accession number :
- 27801882
- Full Text :
- https://doi.org/10.1038/cr.2016.125