Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance

20.01.2015

Ketscher L, Hannß R, Morales DJ, Basters A, Guerra S, Goldmann T, Hausmann A, Prinz M, Naumann R, Pekosz A, Utermöhlen O, Lenschow DJ, Knobeloch KP.

Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1577-82

Proc Natl Acad Sci U S A.         online article

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-in mice (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. 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.