Inhibition of Vpx-Mediated SAMHD1 and Vpr-Mediated Host Helicase Transcription Factor Degradation by Selective Disruption of Viral CRL4 (DCAF1) E3 Ubiquitin Ligase Assembly

Wang, Hong; Guo, Hao; Su, Jiaming; Rui, Yajuan; Zheng, Wenwen; Gao, Wenying; Zhang, Wenyan; Li, Zhaolong; Liu, Guanchen; Markham, Richard B.; Wei, Wei; Yu, Xiao Fang

doi:10.1128/jvi.00225-17

Cited by 23 publications

(24 citation statements)

References 86 publications

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“…Thus, our data support that zinc is not important for the FIV Vif-CUL5 interaction, as discussed previously (18). Other studies have demonstrated that TPEN treatment blocks the function of HIV-1 Vif and Vpr and SIVmac Vpx (39). These findings indicate that in the group of lentiviruses, there are zinc-dependent (e.g., HIV-1 and BIV) and zinc-independent (e.g., FIV and MVV) Vif proteins.…”

Section: Discussionsupporting

confidence: 91%

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Identification of a Conserved Interface of Human Immunodeficiency Virus Type 1 and Feline Immunodeficiency Virus Vifs with Cullin 5

Zhang

Gertzen

et al. 2018

J Virol

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Members of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC3 [A3]) family of DNA cytidine deaminases are intrinsic restriction factors against retroviruses. In felids such as the domestic cat (), the A3 genes encode the A3Z2, A3Z3, and A3Z2Z3 antiviral cytidine deaminases. Only A3Z3 and A3Z2Z3 inhibit viral infectivity factor (Vif)-deficient feline immunodeficiency virus (FIV). The FIV Vif protein interacts with Cullin (CUL), Elongin B (ELOB), and Elongin C (ELOC) to form an E3 ubiquitination complex to induce the degradation of feline A3s. However, the functional domains in FIV Vif for the interaction with Cullin are poorly understood. Here, we found that the expression of dominant negative CUL5 prevented the degradation of feline A3s by FIV Vif, while dominant negative CUL2 had no influence on the degradation of A3. In coimmunoprecipitation assays, FIV Vif bound to CUL5 but not CUL2. To identify the CUL5 interaction site in FIV Vif, the conserved amino acids from positions 47 to 160 of FIV Vif were mutated, but these mutations did not impair the binding of Vif to CUL5. By focusing on a potential zinc-binding motif (K175-C161-C184-C187) of FIV Vif, we found a conserved hydrophobic region (174IR175) that is important for the CUL5 interaction. Mutation of this region also impaired the FIV Vif-induced degradation of feline A3s. Based on a structural model of the FIV Vif-CUL5 interaction, the 52LW53 region in CUL5 was identified as mediating binding to FIV Vif. By comparing our results to the human immunodeficiency virus type 1 (HIV-1) Vif-CUL5 interaction surface (120IR121, a hydrophobic region that is localized in the zinc-binding motif), we suggest that the CUL5 interaction surface in the diverse HIV-1 and FIV Vifs is evolutionarily conserved, indicating a strong structural constraint. However, the FIV Vif-CUL5 interaction is zinc independent, which contrasts with the zinc dependence of HIV-1 Vif. Feline immunodeficiency virus (FIV), which is similar to human immunodeficiency virus type 1 (HIV-1), replicates in its natural host in T cells and macrophages that express the antiviral restriction factor APOBEC3 (A3). To escape A3s, FIV and HIV induce the degradation of these proteins by building a ubiquitin ligase complex using the viral protein Vif to connect to cellular proteins, including Cullin 5. Here, we identified the protein residues that regulate this interaction in FIV Vif and Cullin 5. While our structural model suggests that the diverse FIV and HIV-1 Vifs use conserved residues for Cullin 5 binding, FIV Vif binds Cullin 5 independently of zinc, in contrast to HIV-1 Vif.

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Section: Discussionsupporting

confidence: 91%

“…Three HIV/SIV accessory proteins (Vpr, Vpx, and Vif) bind zinc, which is essential for the assembly of their E3 ligase complexes (39)(40)(41). Zinc is also required for BIV Vif-CUL2 binding, while the MVV Vif-CUL5 interaction does not need zinc (42).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Conserved Interface of Human Immunodeficiency Virus Type 1 and Feline Immunodeficiency Virus Vifs with Cullin 5

Zhang

Gertzen

et al. 2018

J Virol

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“…However, there is little evidence indicating whether such Vpr sequences mimic the full role played by typical HHCC zinc-binding motifs. Recently, some studies have revealed that the HHCH motif of HIV-1 Vpr, which is positioned parallel to that of HIV-2 Vpx, may show capacity to interact with the E3 ligase complex [28]. However, whether the potential zinc-binding motif contributes to the function of Vprs remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…It was suggested that a zinc-binding motif is essential for maintaining both Vpr and Vpx. The potential zinc-binding motif of Vpr/Vpx also engaged E3 ubiquitin ligase complex formation and hijacked it to induce cellular factor degradation [28]. By contrast, flexible C-terminal domains exhibited sequence diversity compared to the central region of Vpr/Vpx proteins.…”

Section: Phylogeny Multiple Alignments and Expression Of Vpr/x Frommentioning

confidence: 99%

Distinct MCM10 Proteasomal Degradation Profiles by Primate Lentiviruses Vpr Proteins

Chang

Siarot

Matsuura

et al. 2020

Viruses

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Viral protein R (Vpr) is an accessory protein found in various primate lentiviruses, including human immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) as well as simian immunodeficiency viruses (SIVs). Vpr modulates many processes during viral lifecycle via interaction with several of cellular targets. Previous studies showed that HIV-1 Vpr strengthened degradation of Mini-chromosome Maintenance Protein10 (MCM10) by manipulating DCAF1-Cul4-E3 ligase in proteasome-dependent pathway. However, whether Vpr from other primate lentiviruses are also associated with MCM10 degradation and the ensuing impact remain unknown. Based on phylogenetic analyses, a panel of primate lentiviruses Vpr/x covering main virus lineages was prepared. Distinct MCM10 degradation profiles were mapped and HIV-1, SIVmus and SIVrcm Vprs induced MCM10 degradation in proteasome-dependent pathway. Colocalization and interaction between MCM10 with these Vprs were also observed. Moreover, MCM10 2-7 interaction region was identified as a determinant region susceptible to degradation. However, MCM10 degradation did not alleviate DNA damage response induced by these Vpr proteins. MCM10 degradation by HIV-1 Vpr proteins was correlated with G2/M arrest, while induction of apoptosis and oligomerization formation of Vpr failed to alter MCM10 proteolysis. The current study demonstrated a distinct interplay pattern between primate lentiviruses Vpr proteins and MCM10.

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“…Moreover, other proteins involved in DNA repair (i.e. uracil-DNA glycosylase 2, single-strand selective monofunctional uracil-DNA glycosylase and more recently the DNA helicase/translocase HLTF) are degraded by Vpr through an E3 ubiquitin ligase complex composed of VPRBP (Vpr binding protein or DCAF), DDB1 and cullin 4A (CUL4A) [ 38 – 40 , 44 , 54 ]. Using the neddylation and CUL4A inhibitor MLN4924 we still observed efficient PHF13 degradation by Vpr.…”

Section: Discussionmentioning

confidence: 99%

Dual role of the chromatin-binding factor PHF13 in the pre- and post-integration phases of HIV-1 replication

et al. 2017

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Viruses interact with multiple host cell factors. Some of these are required to promote viral propagation, others have roles in inhibiting infection. Here, we delineate the function of the cellular factor PHF13 (or SPOC1), a putative HIV-1 restriction factor. Early in the HIV-1 replication cycle PHF13 increased the number of integrated proviral copies and the number of infected cells. However, after HIV-1 integration, high levels of PHF13 suppressed viral gene expression. The antiviral activity of PHF13 is counteracted by the viral accessory protein Vpr, which mediates PHF13 degradation. Altogether, the transcriptional master regulator and chromatin binding protein PHF13 does not have purely repressive effects on HIV-1 replication, but also promotes viral integration. By the functional characterization of the dual role of PHF13 during the HIV-1 replication cycle, we reveal a surprising and intricate mechanism through which HIV-1 might regulate the switch from integration to viral gene expression. Furthermore, we identify PHF13 as a cellular target specifically degraded by HIV-1 Vpr.

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Inhibition of Vpx-Mediated SAMHD1 and Vpr-Mediated Host Helicase Transcription Factor Degradation by Selective Disruption of Viral CRL4 (DCAF1) E3 Ubiquitin Ligase Assembly

Cited by 23 publications

References 86 publications

Identification of a Conserved Interface of Human Immunodeficiency Virus Type 1 and Feline Immunodeficiency Virus Vifs with Cullin 5

Identification of a Conserved Interface of Human Immunodeficiency Virus Type 1 and Feline Immunodeficiency Virus Vifs with Cullin 5

Distinct MCM10 Proteasomal Degradation Profiles by Primate Lentiviruses Vpr Proteins

Dual role of the chromatin-binding factor PHF13 in the pre- and post-integration phases of HIV-1 replication

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