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J. Virol. doi:10.1128/JVI.02285-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

SIAH-1 Interacts with the KSHV-encoded ORF45 Protein and Promotes its Ubiquitylation and Proteasomal Degradation

The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, Israel

^* To whom correspondence should be addressed. Email: saridr{at}mail.biu.ac.il.

	Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV), also referred to as human herpesvirus-8 (HHV-8), is a potentially tumorigenic virus implicated in the etiology of Kaposi's sarcoma, primary effusion lymphoma, and some forms of multicentric Castleman's disease. Open reading frame (ORF) 45 protein, encoded by the KSHV genome, is capable of inhibiting virus-dependent interferon induction and appears to be essential for both early and late stages of infection. In the present study, we show, both in yeast two-hybrid assays and in mammalian cells, that ORF45 protein interacts with the cellular ubiquitin E3 ligase family, ‘seven in absentia homologue' (SIAH). We provide evidence that SIAH-1 promotes the degradation of KSHV ORF45 through a RING domain dependent mechanism and via the ubiquitin-proteasome system. Furthermore, our data indicate the involvement of SIAH-1 in the regulation of the expression of ORF45 in KSHV-infected cells. Since the availability of KSHV ORF45 is expected to influence the course of KSHV infection, our findings identify a novel biological role for SIAH proteins, as modulators of virus infection.