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J. Biol. Chem., Vol. 280, Issue 29, 26933-26940, July 22, 2005

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The Contribution of RING and B-box 2 Domains to Retroviral Restriction Mediated by Monkey TRIM5^*

Hassan Javanbakht¶, Felipe Diaz-Griffero, Matthew Stremlau, Zhihai Si, and Joseph Sodroski||**

From the Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Division of AIDS, Harvard Medical School and the ^||Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115

TRIM5 is a cytoplasmic protein that mediates a post-entry block to infection by some retroviruses. TRIM5 contains a tripartite motif (TRIM), which includes RING, B-box 2, and coiled-coil domains, and a C-terminal B30.2 (SPRY) domain. We investigated the contribution of the RING and B-box 2 domains to the antiretroviral activity of rhesus monkey TRIM5 (TRIM5_rh), which potently restricts infection by human immunodeficiency virus, type 1 (HIV-1) and simian immunodeficiency virus of African green monkeys (SIV_agm). Disruption of the RING domain caused mislocalization of TRIM5_rh so that the cytoplasmic level of the protein was decreased compared with that of the wild-type protein. Nonetheless, partial ability to restrict HIV-1 and SIV_agm was retained by the RING domain mutants. By contrast, although TRIM5_rh mutants with disrupted B-box 2 domains were efficiently expressed and correctly localized to the cytoplasm, antiretroviral activity was absent. The B-box 2 mutants colocalized and associated with wild-type TRIM5_rh and exerted dominant-negative effects on the antiretroviral activity of the wild-type protein. Taken together with other data, these results indicate that functionally defective TRIM5_rh molecules that retain a coiled coil can act as dominant-negative inhibitors of wild-type TRIM5_rh function. The RING domain of TRIM5_rh is not absolutely required for retrovirus restriction but can influence cytoplasmic levels of the protein and thus indirectly alter function. The B-box 2 domain, by contrast, appears to be essential for efficient retrovirus restriction.

Received for publication, February 24, 2005 , and in revised form, May 10, 2005.

^* This work was supported in part by Grants AI063987 and HL54785 from the National Institutes of Health and a Center for AIDS Research Award (AI28691). We also acknowledge the support of the International AIDS Vaccine Initiative, the Bristol-Myers Squibb Foundation, the William A. Haseltine Foundation for the Arts and Sciences, and the late William F. McCarty-Cooper. 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.

^¶ Supported by a fellowship from the Canadian Institutes of Health Research.

^** To whom correspondence should be addressed: Dana-Farber Cancer Institute, 44 Binney St., JFB 824, Boston, MA 02115. Tel.: 617-632-3371; Fax: 671-632-4338; E-mail: joseph_sodroski{at}dfci.harvard.edu.

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