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J. Biol. Chem., Vol. 283, Issue 23, 15681-15688, June 6, 2008

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USP11 Stabilizes HPV-16E7 and Further Modulates the E7 Biological Activity^*

Ching-Hui Lin, Hung-Shu Chang¹, and Winston C. Y. Yu²

From the National Health Research Institutes, 35 Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan and the Department of Life Sciences, National Cheng Kung University, 1 University Rd., Tainan City 701, Taiwan

HPV-16E7 is a major transforming protein, which has been implicated in the development of cervical cancer. The stability of E7 is thus important to ensure its fully functional status. Using the yeast two-hybrid system, we found that USP11 (ubiquitin-specific protease 11), a member of a protein family that cleaves polyubiquitin chains and/or ubiquitin precursors, interacts and forms a specific complex with HPV-16E7. Our results indicate that the USP11 can greatly increase the steady state level of HPV-16E7 by reducing ubiquitination and attenuating E7 degradation. In contrast, a catalytically inactive mutant of USP11 abolished the deubiquitinating ability and returned E7 to a normal rate of degradation. Moreover, USP11 not only protected E7 from ubiquitination but also influenced E7 function as a modulator of cell growth status. These results suggest that USP11 plays an important role in regulating the levels of E7 protein and subsequently affects the biological function of E7 as well as its contribution to cell transformation by HPV-16E7.

Received for publication, October 4, 2007 , and in revised form, March 24, 2008.

^* This work was supported by National Health Research Institutes and National Science Council, Taiwan, Grant NSC96-2320-B-400-006. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–6.

¹ To whom correspondence may be addressed. Tel.: 886-6-2757575; Fax: 886-6-2742583; E-mail: hschang{at}mail.ncku.edu.tw. ² To whom correspondence may be addressed. Tel.: 886-37-246-166 (ext. 31710); Fax: 886-37-586-463; E-mail: winston{at}nhri.org.tw.

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