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J. Biol. Chem., Vol. 281, Issue 7, 3989-3994, February 17, 2006

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The Interferon-inducible Ubiquitin-protein Isopeptide Ligase (E3) EFP Also Functions as an ISG15 E3 Ligase^*

From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

The expression of the ubiquitin-like protein ISG15 and protein modification by ISG15 (ISGylation) are strongly activated by interferons. Accordingly, ISG15 expression and protein ISGylation are strongly activated upon viral and bacterial infections and during other stress conditions, suggesting important roles for the ISG15 system in innate immune responses. Here, we report the identification of the ubiquitin-protein isopeptide ligase (E3) EFP (estrogen-responsive finger protein) as the ISG15 E3 ligase for 14-3-3 protein. Like other known components of the protein ISGylation system (ISG15, UBE1L, UBP43, and UBC8), EFP is also an interferon-inducible protein. Expression of EFP small interfering RNA decreased the ISGylation of 14-3-3 in the 293T cell ISGylation system as well as in MCF-7 cells upon interferon treatment. Furthermore, the ISGylation enzyme activity of EFP was RING domain-dependent. These findings indicate that EFP is an ISG15 E3 ligase for 14-3-3 in vivo. The fact that both UBC8 and EFP are common components in the ubiquitin and ISG15 conjugation pathways suggests a mechanism whereby a limited set of enzymes accomplishes diverse post-translational modifications of their substrates in response to changes in environmental stimulations.

Received for publication, October 3, 2005 , and in revised form, December 1, 2005.

^* This work was supported in part by National Institutes of Health Grants CA079849 and GM066955 (to D.-E. Z.). The DNA sequencing and oligonucleotide synthesis done by the departmental molecular biology service laboratory was supported in part by the Stein Endowment Fund. This is Manuscript MEM-17282 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 Leukemia and Lymphoma Society Fellow.

² To whom correspondence should be addressed: Dept. of Molecular and Experimental Medicine, The Scripps Research Inst., Mail Drop MEM-L51, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-9558; Fax: 858-784-9593; E-mail: dzhang{at}scripps.edu.

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