The HIV-1 Vpr and glucocorticoid receptor complex is a gain-of-function interaction that prevents the nuclear localization of PARP-1

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  • A Corrigendum to this article was published on 01 March 2006

Abstract

The Vpr protein of HIV-1 functions as a vital accessory gene by regulating various cellular functions, including cell differentiation, apoptosis, nuclear factor of κB (NF-κB) suppression and cell-cycle arrest of the host cell. Several reports have indicated that Vpr complexes with the glucocorticoid receptor (GR), but it remains unclear whether the GR pathway is required for Vpr to function1. Here, we report that Vpr uses the GR pathway as a recruitment vehicle for the NF-κB co-activating protein, poly(ADP-ribose) polymerase-1 (PARP-1). The GR interaction with Vpr is both necessary and sufficient to facilitate this interaction by potentiating the formation of a Vpr–GR–PARP-1 complex. The recruitment of PARP-1 by the Vpr–GR complex prevents its nuclear localization, which is necessary for Vpr to suppress NF-κB. The association of GR with PARP-1 is not observed with steroid (glucocorticoid) treatment, indicating that the GR association with PARP-1 is a gain of function that is solely attributed to HIV-1 Vpr. These data provide important insights into Vpr biology and its role in HIV pathogenesis.

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Figure 1: Vpr transcriptionally suppresses NF-κB through a pathway that does not require a functional glucocorticoid receptor.
Figure 2: Vpr interacts with PARP-1 and inhibits its nuclear localization through a GR interaction-dependent pathway.
Figure 3: The GR interaction with Vpr is both necessary and sufficient to recruit PARP-1.
Figure 4: Recruitment of PARP-1 to the Vpr–GR complex is necessary for Vpr-mediated transcriptional suppression of NF-κB.
Figure 5: The PARP-1–Vpr–GR interaction is relevant in vivo.

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Acknowledgements

PARP-1 expression vector was generously provided by Z.-Q. Wang (IARC, Lyon, France) and p65/RelA expression constructs were gifts from D.R. Green (La Jolla Institute for Allergy and Immunology, San Diego, CA). We thank M.A. Chattergoon and D.J. Laddy for their useful comments, and M.J. Merva for administrative assistance. Support from the National Institutes of Health (NIH) AIDS Research and Reference Reagents program and Centers for AIDS Research (CFAR), University of Pennsylvania, is also acknowledged. This work was supported by grants from the NIH to D.B.W.

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Correspondence to David B. Weiner.

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