期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 5, 页码 1577-1582出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1412881112
关键词
ISG15; UBP43; interferon; ubiquitin isopeptidase; influenza
资金
- Deutsche Forschungsgemeinschaft (DFG) [KN590/1-2, KN590/3-1, KN590/3-2, FOR1336, SFB 942, PR 577/8-2]
- National Institutes of Health (NIH) [R01 AI080672]
- Pew Scholar Award
- NIH Training Grant GM [007067]
- Spanish Ministry of Health [FIS2011-00127]
- Speed Congenics Facility of the Rheumatic Diseases Core Center [P30AR048335]
- Bundesministerium fur Bildung und Forschung (Krankheitsbezogenes Kompetenznetz Multiple Sklerose)
Protein modification by the ubiquitin-like protein ISG15 is an interferon (IFN) effector system, which plays a major role in antiviral defense. ISG15 modification is counteracted by the isopeptidase USP18, a major negative regulator of IFN signaling, which was also shown to exert its regulatory function in an isopeptidase-independent manner. To dissect enzymatic and nonenzymatic functions of USP18 in vivo, we generated knock-inmice (USP18(C61A/C61A)) expressing enzymatically inactive USP18. USP18(C61A/C61A) mice displayed increased levels of ISG15 conjugates, validating that USP18 is a major ISG15 isopeptidase in vivo. Unlike USP18(-/-) mice, USP18(C61A/C61A) animals did not exhibit morphological abnormalities, fatal IFN hypersensitivity, or increased lethality, clearly showing that major USP18 functions are unrelated to its protease activity. Strikingly, elevated ISGylation in USP18(C61A/C61A) mice was accompanied by increased viral resistance against vaccinia virus and influenza B virus infections. Enhanced resistance upon influenza B infection in USP18(C61A/C61A) mice was completely reversed in USP18(C61A/C61A) mice, which additionally lack ISG15, providing evidence that the observed reduction in viral titers is ISG15 dependent. These results suggest that increasing ISGylation by specific inhibition of USP18 protease activity could constitute a promising antiviral strategy with only a minimal risk of severe adverse effects.
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