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:
CreatorsEmailORCIDORCID Put Code
Ketscher, LarsUNSPECIFIEDorcid.org/0000-0002-5093-4931UNSPECIFIED
Hannss, RonnyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morales, David J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Basters, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerra, SusanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldmann, TobiasUNSPECIFIEDorcid.org/0000-0001-9754-9144UNSPECIFIED
Hausmann, AnnikaUNSPECIFIEDorcid.org/0000-0001-8852-3444UNSPECIFIED
Prinz, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naumann, RonaldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pekosz, AndrewUNSPECIFIEDorcid.org/0000-0003-3248-1761UNSPECIFIED
Utermoehlen, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lenschow, Deborah J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knobeloch, Klaus-PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
UBIQUITIN-LIKE PROTEIN; NS1 PROTEIN; UBP43 USP18; E3 PROTEIN; VIRUS; ENZYME; ISGYLATION; INFLUENZA; INFECTION; TARGETSMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/40781

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