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J. Biol. Chem., Vol. 279, Issue 52, 54110-54116, December 24, 2004

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The Poxvirus p28 Virulence Factor Is an E3 Ubiquitin Ligase^*

Jianing Huang, Qi Huang, Xiulan Zhou, Mary M. Shen, Ann Yen, Simon X. Yu, GuoQiang Dong, Kunbin Qu, Peiyong Huang, Emily M. Anderson, Sarkiz Daniel-Issakani, R. Mark L. Buller¶, Donald G. Payan||, and H. Henry Lu||

From the Rigel Pharmaceuticals, Inc., South San Francisco, California 94080 and the ^¶Department of Molecular Microbiology and Immunology, St. Louis University Health Sciences Center, St. Louis, Missouri 63104

A majority of the orthopoxviruses, including the variola virus that causes the dreaded smallpox disease, encode a highly conserved 28-kDa protein with a classic RING finger sequence motif (C₃HC₄) at their carboxyl-terminal domains. The RING domain of p28 has been shown to be a critical determinant of viral virulence for the ectromelia virus (mousepox virus) in a murine infection model (Senkevich, T. G., Koonin, E. V., and Buller, R. M. (1994) Virology 198, 118–128). Here, we demonstrate that the p28 proteins encoded by the ectromelia virus and the variola virus possess E3 ubiquitin ligase activity in biochemical assays as well as in cultured mammalian cells. Point mutations disrupting the RING finger domain of p28 completely abolish its E3 ligase activity. In addition, p28 functions cooperatively with Ubc4 and UbcH5c, the E2 conjugating enzymes involved in 26 S proteasome degradation of protein targets. Moreover, p28 catalyzes the formation of Lys-63-linked polyubiquitin chains in the presence of Ubc13/Uev1A, a heterodimeric E2 conjugating enzyme, indicating that p28 may regulate the biological activity of its cognate viral and/or host cell target(s) by Lys-63-linked ubiquitin multimers. We thus conclude that the poxvirus p28 virulence factor is a new member of the RING finger E3 ubiquitin ligase family and has a unique polyubiquitylation activity. We propose that the E3 ligase activity of the p28 virulence factor may be targeted for therapeutic intervention against infections by the variola virus and other poxviruses.

Received for publication, September 14, 2004

^* 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.

Both authors contributed equally to this work.

^|| To whom correspondence may be addressed: Rigel Pharmaceuticals, Inc., 1180 Veterans Blvd., South San Francisco, CA 94080. Tel.: 650-624-1102; E-mail: dgpayan{at}rigel.com. ** To whom correspondence may be addressed: Rigel Pharmaceuticals, Inc., 1180 Veterans Blvd., South San Francisco, CA 94080. Tel.: 650-624-1331; Fax: 650-624-1101; E-mail: hlu{at}rigel.com.

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