Title: Differential interaction of HIV-1 integrase and JPO2 with the C Terminus of LEDGF/p75
Authors: Bartholomeeusen, Koen ×
De Rijck, Jan
Busschots, Katrien
Desender, Linda
Gijsbers, Rik
Emiliani, Stéphane
Benarous, Richard
Debyser, Zeger
Christ, Frauke #
Issue Date: 28-Sep-2007
Series Title: Journal of Molecular Biology vol:372 issue:2 pages:407-421
Abstract: The transcriptional co-activator lens epithelium-derived growth factor (LEDGF) has been shown to protect cells against environmental stress. The protein has been implicated in auto-immunity and cancer, and is present in cells as the p52 or p75 splice variant. Recently, LEDGF/p75, but not p52, was identified as the prominent interaction partner of human immunodeficiency virus type 1 (HIV-1) integrase. This interaction of HIV-1 integrase with the C-terminal integrase-binding domain of LEDGF/p75 is crucial for HIV-1 replication. To gain insight into the cell biology of LEDGF/p75, we were interested in identifying cellular binding partners of its C-terminal domain. By yeast-two-hybrid screening with a CEMC7 cDNA-library, we were able to identify JPO2 as a binding partner of the C-terminal part of LEDGF/p75. The specific interaction between JPO2 and LEDGF/p75 was verified by pull-down, AlphaScreen, and co-immunoprecipitation. Competition assays using recombinant proteins show a mutually exclusive binding of either JPO2 or HIV-1 integrase to LEDGF/p75. However, differing mechanisms of binding were suggested by continuing interaction of JPO2 with some LEDGF/p75 mutants (I365A, D366A, F406A) that are totally defective for interaction with HIV-1 integrase. This finding is of significance for the development of specific inhibitors targeting only the interaction between LEDGF/p75 and HIV-1 integrase, without disturbing interaction with other cellular factors. Over-expression of JPO2 resulted in a modest but reproducible inhibition of HIV-1 replication, consistent with competition between integrase and JPO2 for binding to LEDGF/p75. Furthermore, JPO2 over-expression activated transcription from the HIV-1 LTR.
ISSN: 0022-2836
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Biochemistry, Kulak (-)
Faculty of Medicine, Campus Kulak Kortrijk
Molecular Virology and Gene Therapy
× corresponding author
# (joint) last author

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