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Molecular and Cellular Biology, August 2005, p. 6338-6345, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6338-6345.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

ISG15, an Interferon-Stimulated Ubiquitin-Like Protein, Is Not Essential for STAT1 Signaling and Responses against Vesicular Stomatitis and Lymphocytic Choriomeningitis Virus

Anna Osiak,1 Olaf Utermöhlen,3 Sandra Niendorf,1 Ivan Horak,1,2 and Klaus-Peter Knobeloch1*

Abteilung für Molekulare Genetik, Institut für Molekulare Pharmakologie,1 Charité Universitätsmedizin, Berlin, Germany,2 Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Universität Köln, Köln, Germany3

Received 20 December 2004/ Returned for modification 7 March 2005/ Accepted 1 May 2005

ISG15 is an interferon-induced ubiquitin-like modifier which can be conjugated to distinct, but largely unknown, proteins. ISG15 has been implicated in a variety of biological activities, which encompass antiviral defense, immune responses, and pregnancy. Mice lacking UBP43 (USP18), the ISG15-deconjugating enzyme, develop a severe phenotype with brain injuries and lethal hypersensitivity to poly(I:C). It has been reported that an augmented conjugation of ISG15 in the absence of UBP43 induces prolonged STAT1 phosphorylation and that the ISG15 conjugation plays an important role in the regulation of JAK/STAT and interferon signaling (O. A. Malakhova, M. Yan, M. P. Malakhov, Y. Yuan, K. J. Ritchie, K. I. Kim, L. F. Peterson, K. Shuai, and D. E. Zhang, Genes Dev. 17:455-460, 2003). Here, we report that ISG15–/– mice are viable and fertile and display no obvious abnormalities. Lack of ISG15 did not affect the development and composition of the main cellular compartments of the immune system. The interferon-induced antiviral state and immune responses directed against vesicular stomatitis virus and lymphocytic choriomeningitis virus were not significantly altered in the absence of ISG15. Furthermore, interferon- or endotoxin-induced STAT1 tyrosine-phosphorylation, as well as expression of typical STAT1 target genes, remained unaffected by the lack of ISG15. Thus, ISG15 is dispensable for STAT1 and interferon signaling.

* Corresponding author. Mailing address: Institute of Molecular Pharmacology, Department of Molecular Genetics, Krahmerstr. 6, 12207 Berlin, Germany. Phone: 49 3084371915. Fax: 49 3084371922. E-mail: knobeloch{at}fmp-berlin.de.

Molecular and Cellular Biology, August 2005, p. 6338-6345, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6338-6345.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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