Universität zu Köln

Ketscher, Lars ORCID: 0000-0002-5093-4931, Hannss, Ronny, Morales, David J., Basters, Anja, Guerra, Susana, Goldmann, Tobias ORCID: 0000-0001-9754-9144, Hausmann, Annika ORCID: 0000-0001-8852-3444, Prinz, Marco, Naumann, Ronald, Pekosz, Andrew ORCID: 0000-0003-3248-1761, Utermoehlen, Olaf, Lenschow, Deborah J. and Knobeloch, Klaus-Peter (2015). Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance. Proc. Natl. Acad. Sci. U. S. A., 112 (5). S. 1577 - 1583. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ketscher, Lars UNSPECIFIED orcid.org/0000-0002-5093-4931 UNSPECIFIED Hannss, Ronny UNSPECIFIED UNSPECIFIED UNSPECIFIED Morales, David J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Basters, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Guerra, Susana UNSPECIFIED UNSPECIFIED UNSPECIFIED Goldmann, Tobias UNSPECIFIED orcid.org/0000-0001-9754-9144 UNSPECIFIED Hausmann, Annika UNSPECIFIED orcid.org/0000-0001-8852-3444 UNSPECIFIED Prinz, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Naumann, Ronald UNSPECIFIED UNSPECIFIED UNSPECIFIED Pekosz, Andrew UNSPECIFIED orcid.org/0000-0003-3248-1761 UNSPECIFIED Utermoehlen, Olaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Lenschow, Deborah J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Knobeloch, Klaus-Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-407818
DOI:	10.1073/pnas.1412881112
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	112
Number:	5
Page Range:	S. 1577 - 1583
Date:	2015
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language UBIQUITIN-LIKE PROTEIN; NS1 PROTEIN; UBP43 USP18; E3 PROTEIN; VIRUS; ENZYME; ISGYLATION; INFLUENZA; INFECTION; TARGETS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40781