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J. Biol. Chem., Vol. 283, Issue 36, 24484-24488, September 5, 2008

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Nitrosylation of ISG15 Prevents the Disulfide Bond-mediated Dimerization of ISG15 and Contributes to Effective ISGylation^*

Fumihiko Okumura¹, Deborah J. Lenschow, and Dong-Er Zhang^¶2

From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, Departments of Internal Medicine, Pathology, and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, and ^¶Moores Cancer Center, Department of Pathology, and Division of Biological Sciences, University of California San Diego, La Jolla, California 92093

The expression of the ubiquitin-like molecule ISG15 (UCRP) and protein modification by ISG15 (ISGylation) are strongly activated by interferon, genotoxic stress, and pathogen infection, suggesting that ISG15 plays an important role in innate immune responses. Inducible nitric-oxide synthase (iNOS) is induced by the similar stimuli as ISG15 and enhances the production of nitric oxide (NO), a pleiotropic free radical with antipathogen activity. Here, we report that cysteine residues (Cys-76 and -143 in mouse, Cys-78 in human) of ISG15 can be modified by NO, and the NO modification of ISG15 decreases the dimerization of ISG15. The mutation of the cysteine residue of ISG15 to serine improves total ISGylation. The NO synthase inhibitor S-ethylisothiourea reduces endogenous ISGylation. Furthermore, ectopic expression of iNOS enhanced total ISGylation. Together, these results suggest that nitrosylation of ISG15 enhances target protein ISGylation. This is the first report of a relationship between ISGylation and nitrosylation.

Received for publication, May 19, 2008 , and in revised form, July 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM66955 and CA102625 (to D.-E. Z.). This work was also supported by a Uehara Memorial Foundation postdoctoral fellowship (to F. O.). This is manuscript 19193 from The Scripps Research Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Biochemistry, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku, Sapporo 060-8638, Japan.

² To whom correspondence should be addressed: Mail Stop 0815, Rm. 5328, Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Dr., La Jolla, CA 92093. Tel.: 858-822-5372; Fax: 858-822-5433; E-mail: d7zhang{at}ucsd.edu.

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