Human Immunodeficiency Virus Type 1 (HIV-1) Accessory Protein Vpr Induces Transcription of the HIV-1 and Glucocorticoid-Responsive Promoters by Binding Directly to p300/CBP Coactivators

Abstract

The accessory Vpr protein of human immunodeficiency virus type 1 (HIV-1) is a promiscuous activator of viral and cellular promoters. We report that Vpr enhances expression of the glucocorticoid receptor-induced mouse mammary tumor virus (MMTV) promoter and of the Tat-induced HIV-1 long terminal repeat promoter by directly binding to p300/CBP coactivators. In contrast, Vpr does not bind to p/CAF or to members of the p160 family of nuclear receptor coactivators, such as steroid receptor coactivator 1a and glucocorticoid receptor (GR)-interacting protein 1. Vpr forms a stable complex with p300 and also interacts with the ligand-bound glucocorticoid receptor in vivo. Mutation analysis showed that the C-terminal part of Vpr binds to the C-terminal portion of p300/CBP within amino acids 2045 to 2191. The same p300 region interacts with the p160 coactivators and with the adenovirus E1A protein. Accordingly, E1A competed for binding to p300 in vitro. Coexpression of E1A or of small fragments of p300 containing the Vpr binding site resulted in inhibition of Vpr's transcriptional effects. The C-terminal part of p300 containing the transactivating region is required for Vpr transactivation, whereas the histone acetyltransferase enzymatic region is dispensable. Vpr mutants that bind p300 but not the GR did not activate expression of the MMTV promoter and had dominant-negative effects. These results indicate that Vpr activates transcription by acting as an adapter linking transcription components and coactivators.

Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

“…Recently a glucocorticoid receptor complex was identified as an intracellular target for Vpr (58,59) suggesting their possible involvement in Vpr-(52-96)-induced apoptosis. The observations that both glucocorticoids (60) and Vpr inhibited NFB induction suggest a role for glucocorticoid receptors in Vpr-mediated apoptosis.…”

HIV-1 Protein Vpr Suppresses IL-12 Production from Human Monocytes by Enhancing Glucocorticoid Action: Potential Implications of Vpr Coactivator Activity for the Innate and Cellular Immunity Deficits Observed in HIV-1 Infection

“…We further demonstrated that Vpr behaved as an adaptor molecule between promoter-bound transcription factors and p300/CBP coactivators in a glucocorticoid-responsive promoter (42). We also reported that nuclear receptor-responsive promoters employed the same set of coactivators and transcription-elongation complexes as the HIV-1 long terminal repeat, and that Vpr potentiated both types of promoter activities through the same mechanism, cooperating with host coactivators (43).…”

Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin

“…Vpr can induce several promoters, including the HIV-1 LTR and p21 WAF1 (Wang et al, 1995;Amini et al, 2004). These studies suggest that cooperativity between several cellular proteins including Sp1 (Wang et al, 1995), p300 (Kino et al, 2002) and p53 (Sawaya et al, 1998) is necessary for Vpr-induced regulation of the HIV-LTR. Vpr was also shown to cause cell differentiation and DNA damage (Shimura et al, 1999a, b).…”