CRL4-DCAF1 Ubiquitin Ligase Dependent Functions of HIV Viral Protein R and Viral Protein X

Abstract

The Human Immunodeficiency Virus (HIV) encodes several proteins that contort the host cell environment to promote viral replication and spread. This is often accomplished through the hijacking of cellular ubiquitin ligases. These reprogrammed complexes initiate or enhance the ubiquitination of cellular proteins that may otherwise act to restrain viral replication. Ubiquitination of target proteins may alter protein function or initiate proteasome-dependent destruction. HIV Viral Protein R (Vpr) and the related HIV-2 Viral Protein X (Vpx), engage the CRL4-DCAF1 ubiquitin ligase complex to target numerous cellular proteins. In this review we describe the CRL4-DCAF1 ubiquitin ligase complex and its interactions with HIV Vpr and Vpx. We additionally summarize the cellular proteins targeted by this association as well as the observed or hypothesized impact on HIV.

Keywords: CRL4; DCAF1; G2 arrest; HIV; HuSH; SAMHD1; UNG2; Vpr; Vpx; ubiquitin.

Figure 1

Overview of the CRL4-DCAF1 Ubiquitin Ligase Complex. Created with BioRender.com.

Figure 2

Interaction properties of HIV-1 Vpr. (A) Amino acid sequences of HIV-1 Vpr from HIV-1 89.6 (accension Q73369) and HIV-2 Vpr and Vpx from HIV-2 ROD (accension P06938 and P06939, respectively). (B) Ribbon and stick representations of HIV-1 Vpr (from PDB 1M8L). Key residues, motifs, and domains for the indicated interactions are color coded and/or bolded and/or labeled for each panel. Ribbon and stick representations were created with the PyMOL Molecular Graphics System, Version 2.5.5. This figure was assembled with BioRender.com.

Figure 3

Summary of DCAF1-dependent HIV Vpr and Vpx targets. Cellular targets are grouped by the cellular and/or viral function/phenotype for which they are associated. Each target is accompanied by a brief summary of their possible role in antagonizing HIV replication. Of note, targets may be associated with more than one function/phenotype, and color coding is based on the function/phenotype for which they are initially described. For each category, targets are generally listed in the order in which they appear in the review. Targets of HIV Vpr are discussed in Section 3 and Section 5. Targets associated with HIV-2 Vpx are discussed in Section 4. (#.#) denotes the corresponding subsection in which that target is discussed. DDR = DNA Damage Response. This figure was created with BioRender.com.

Figure 4

Interaction properties of HIV-2 Vpx. (A) Amino acid sequences of HIV-1 Vpr from HIV-1 89.6 (accension Q73369) and HIV-2 Vpr and Vpx from HIV-2 ROD (accension P06938 and P06939, respectively). (B) Ribbon and stick representations of SIVsmm Vpx (a close ortholog of HIV-2 Vpx) (from PDB 4CC9). Key residues, motifs, and domains for the indicated interactions are color coded and/or bolded and/or labeled for each panel. Ribbon and stick representations were created with the PyMOL Molecular Graphics System, Version 2.5.5. This figure was assembled with BioRender.com.