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Originally published In Press as doi:10.1074/jbc.M004670200 on July 12, 2000

J. Biol. Chem., Vol. 275, Issue 38, 29749-29753, September 22, 2000
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Degradation of HIV-1 Integrase by the N-end Rule Pathway*

Lubbertus C. F. Mulder and Mark A. MuesingDagger

From the Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016

Human immunodeficiency virus type-1 (HIV-1) integrase catalyzes the irreversible insertion of the viral genome into host chromosomal DNA. We have developed a mammalian expression system for the synthesis of authentic HIV-1 integrase in the absence of other viral proteins. Integrase, which bears a N-terminal phenylalanine, was found to be a short-lived protein in human embryo kidney 293T cells. The degradation of integrase could be suppressed by proteasome inhibitors. N-terminal phenylalanine is recognized as a degradation signal by a ubiquitin-proteasome proteolytic system known as the N-end rule pathway. The replacement of N-terminal phenylalanine with methionine, valine, or glycine, which are stabilizing residues in the N-end rule, resulted in metabolically stabilized integrase proteins (half-life of N-terminal Met-integrase was at least 3 h). Conversely, the substitution of N-terminal phenylalanine with other destabilizing residues retained the metabolic instability of integrase. These findings indicate that the HIV-1 integrase is a physiological substrate of the N-end rule. We discuss a possible functional similarity to the better understood turnover of the bacteriophage Mu transposase and functions of integrase instability to the maintenance and integrity of the host cell genome.

* This work was supported by Columbia-Rockefeller Center for AIDS Research Grant P30 AI42848 (to M. A. M.) from NIAID, National Institutes of Health and by internal funding from the Aaron Diamond AIDS Research Center.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Aaron Diamond AIDS Research Center, Rockefeller University, 455 First Ave., New York, NY 10016. Tel.: 212-448-5060; Fax: 212-448-5159; E-mail: mmuesing@adarc.org.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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