The functions of the HIV1 protein Vpr and its action through the DCAF1.DDB1.Cullin4 ubiquitin ligase

Abstract

Among the proteins encoded by human and simian immunodeficiency viruses (HIV and SIV) at least three, Vif, Vpu and Vpr, subvert cellular ubiquitin ligases to block the action of anti-viral defenses. This review focuses on Vpr and its HIV2/SIV counterparts, Vpx and Vpr, which all engage the DDB1.Cullin4 ubiquitin ligase complex through the DCAF1 adaptor protein. Here, we discuss the multiple functions that have been linked to Vpr expression and summarize the current knowledge on the role of the ubiquitin ligase complex in carrying out a subset of these activities.

Fig. 1

A. Amino acid sequence alignment of HIV1 Vpr and HIV2 Vpr/Vpx. HIV1 Vpr shares about 50% and 25% protein sequence identity with HIV2/SIV_mac Vpr and Vpx, respectively [78, 81]. The region of HIV1 Vpr and HIV2 Vpr that overlaps with Tat is shaded in purple and the region of HIV1 Vpr and HIV2 Vpx that overlaps with Vif is shaded in grey. The amino acids that are predicted to form three alpha-helices are indicated. B. Proviral genome structure of HIV. Vpr is encoded by a reading frame in the center of the HIV1 genome that overlaps both vif and tat reading frames. HIV2 and the closely related virus SIVsmm/mac encode two vpr-like genes, vpx and vpr. C. The functions of Vpr. HIV1 Vpr is a multi-functional protein whose functions segregate to HIV2 Vpr or Vpx.

Fig. 2

A. Overview of DCAF1•DDB1•Cul4 ubiquitin ligase complex. Cullin 4 assembles with a multi-subunit complex to ubiquitylate targeted proteins. Cul4 C terminus associates with a small RING protein, ROC, that recruits and activates an E2 enzyme, while the N terminus of Cul4 interacts with a linker protein, DDB1 that binds the adaptor protein, DCAF1 that interacts with HIV1 Vpr, HIV2 Vpr or HIV2/SIV Vpx. B. The role of the ubiquitin ligase complex in Vpr function. Evidence supports a model in which Vpr/Vpx directs the DDB1•Cul4 ubiquitin ligase complex to ubiquitinate (1) a cellular uracil N glycosylase, UNG2, (2) a cellular protein required for cell cycle progression into mitosis, (3) a cellular protein that is degraded to activate ATR signaling and increases cell surface NKG2D ligands to enhance NK cell-mediated killing, and (4) a cellular antiviral factor that inhibits viral reverse transcription in macrophages.