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J. Biol. Chem., Vol. 278, Issue 35, 33528-33539, August 29, 2003
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LEDGF/p75 Is Essential for Nuclear and Chromosomal Targeting of HIV-1 Integrase in Human Cells*
From the
Laboratory of Biomolecular Dynamics,
Katholieke Universiteit Leuven, Celestijnenlaan 200D, B-3001 Leuven and the
¶Rega Institute for Medical Research, Katholieke
Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
We have reported that human immunodeficiency virus type 1 (HIV-1) integrase (IN) forms a specific nuclear complex with human lens epithelium-derived growth factor/transcription co-activator p75 (LEDGF/p75) protein. We now studied the IN-LEDGF/p75 interaction and nuclear import of IN in living cells using fusions of IN and LEDGF/p75 with enhanced green fluorescent protein and far-red fluorescent protein HcRed1. We show that both the N-terminal zinc binding domain and the central core domains of IN are involved in the interaction with LEDGF/p75. Both domains are essential for nuclear localization of IN as well as for the association of IN with condensed chromosomes during mitosis. However, upon overexpression of LEDGF/p75, the core domain fragment of IN was recruited to the nuclei and mitotic chromosomes with a distribution pattern characteristic of the full-length protein, indicating that it harbors the main determinant for interaction with LEDGF/p75. Although the C-terminal domain of IN was dispensable for nuclear/chromosomal localization, a fusion of the C-terminal IN fragment with enhanced green fluorescent protein was found exclusively in the nucleus, with a diffuse nuclear/nucleolar distribution, suggesting that the C-terminal domain may also play a role in the nuclear import of IN. In contrast to LEDGF/p75, its alternative splice variant, p52, did not interact with HIV-1 IN in vitro and in living cells. Finally, RNA interference-mediated knock-down of endogenous LEDGF/p75 expression abolished nuclear/chromosomal localization of IN. We conclude, therefore, that the interaction with LEDGF/p75 accounts for the karyophilic properties and chromosomal targeting of HIV-1 IN.
Received for publication, April 7, 2003 , and in revised form, June 5, 2003.
* Work at the Rega Institute and in the Laboratory of Biomolecular Dynamics was supported by Concerted Research Action Fund Grant GOA/2001/02 from the Flemish Government. 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.
Aspirant of the Fund for Scientific Research Flanders (Fonds voor
Wetenschappelijk Onderzoek Flanders).
|| Postdoctoral fellow of the Fund for Scientific Research Flanders (Fonds voor Wetenschappelijk Onderzoek Flanders).
** To whom correspondence may be addressed. Tel.: 32-16-332160; Fax: 32-16-332131; E-mail: zeger.debyser{at}med.kuleuven.ac.be.
To whom correspondence may be addressed. Tel.: 32-16-327160; Fax:
32-16-327974; E-mail:
yves.engelborghs{at}fys.kuleuven.ac.be.
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