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

Karuppiah Muthumani¹, Andrew Y. Choo^1, 2, Wei-Xing Zong³, Muniswamy Madesh³, Daniel S. Hwang¹, Arumugam Premkumar⁴, Khanh P. Thieu¹, Joann Emmanuel¹, Sanjeev Kumar¹, Craig B. Thompson³ & David B. Weiner¹

¹  Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

²  Present Address: Program for Biological and Biomedical Sciences (BBS), Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

³  Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

⁴  Laboratory of Molecular Neuropharmacology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

The Vpr protein of HIV-1 functions as a vital accessory gene by regulating various cellular functions, including cell differentiation, apoptosis, nuclear factor of B (NF-B) 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-B 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-B. 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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