Reactome: A Curated Pathway Database
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Interactions of Vpr with host cellular proteins

Stable Identifier
R-HSA-176033
Type
Pathway
Species
Homo sapiens
Locations in the PathwayBrowser
Summation

Vpr has been implicated in multiple processes during HIV-1 replication, including nuclear import of the pre-integration complex (PIC)(Heinzinger et al., 1994), apoptosis (Stewart et al., 1997) and induction of cell cycle G2/M arrest (He et al., 1995; Re et al., 1995; Zhao et al., 1996).

Interactions between Vpr and host nucleoporins (importin) appear to facilitate the nuclear import of the PIC (Popov et al., 1998; Vodicka et al., 1998) while interactions between Vpr the adenine nucleotide transporter (ANT) protein at the inner mitochondrial membrane may contribute to release of apoptosis factors by promoting permeabilization of the mitochondrial outer membrane (Jacotot et al., 2000).

Vpr induces cell cycle G2/M arrest by promoting hyperphosphorylation of Cdk1/Cdc2 (Re et al., 1995; Zhao et al., 1996). However, it is unclear which protein(s) Vpr interacts with to cause this effect. For recent reviews, see, (Li et al., 2005; Zhao, Bukrinsky, and Elder, 2005). Progression of cells from G2 phase of the cell cycle to mitosis is a tightly regulated cellular process that requires activation of the Cdk1/Cdc2 kinase, which determines onset of mitosis in all eukaryotic cells. The activity of Cdk1/Cdc2 is regulated in part by the phosphorylation status of tyrosine 15 (Tyr15) on Cdk1/Cdc2, which is phosphorylated by Wee1 kinase during late G2 and is rapidly dephosphorylated by the Cdc25 tyrosine phosphatase to trigger entry into mitosis. These Cdk1/Cdc2 regulators are the downstream targets of two well-characterized G2/M checkpoint pathways which prevent cells from entering mitosis when cellular DNA is damaged or when DNA replication is inhibited. It is clear that Vpr induces cell cycle G2/M arrest by promoting Tyr15 phosphorylation of Cdk1/Cdc2 both in human and fission yeast cells (Elder et al., 2000; Re et al., 1995; Zhao et al., 1996), which modulates host cell cycle machinery to benefit viral survival or replication. Although some aspects of Vpr-induced G2/M arrest resembles induction of host cellular checkpoints, increasing evidence suggests that Vpr induces cell cycle G2 arrest through a mechanism that is to some extent different from the classic G2/M checkpoints. One the unique features distinguishing Vpr-induced G2 arrest from the classic checkpoints is the role of phosphatase 2A (PP2A) in Vpr-induced G2 arrest (Elder, Benko, and Zhao, 2002; Elder et al., 2001; Masuda et al., 2000). Interestingly, PP2A is targeted by a number of other viral proteins including SV40 small T antigen, polyomavirus T antigen, HTLV Tax and adenovirus E4orf4. Thus an in-depth understanding of the molecular mechanisms underlying Vpr-induced G2 arrest will provide additional insights into the basic biology of cell cycle G2/M regulation and into the biological significance of this effect during host-pathogen interactions.

Literature References
PubMed ID Title Journal Year
10958988 Cell cycle G2 arrest induced by HIV-1 Vpr in fission yeast (Schizosaccharomyces pombe) is independent of cell death and early genes in the DNA damage checkpoint Virus Res 2000
8709199 Effect of human immunodeficiency virus type 1 protein R (vpr) gene expression on basic cellular function of fission yeast Schizosaccharomyces pombe J Virol 1996
10684278 Genetic studies with the fission yeast Schizosaccharomyces pombe suggest involvement of wee1, ppa2, and rad24 in induction of cell cycle arrest by human immunodeficiency virus type 1 Vpr J Virol 2000
11815283 HIV-1 VPR modulates cell cycle G2/M transition through an alternative cellular mechanism other than the classic mitotic checkpoints Front Biosci 2002
11531413 HIV-1 Vpr induces cell cycle G2 arrest in fission yeast (Schizosaccharomyces pombe) through a pathway involving regulatory and catalytic subunits of PP2A and acting on both Wee1 and Cdc25 Virology 2001
9436978 HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection Genes Dev 1998
15817944 HIV-1 viral protein R (Vpr) & host cellular responses Indian J Med Res 2005
7474100 Human immunodeficiency virus type 1 Vpr arrests the cell cycle in G2 by inhibiting the activation of p34cdc2-cyclin B J Virol 1995
9188632 Human immunodeficiency virus type 1 Vpr induces apoptosis following cell cycle arrest J Virol 1997
7474080 Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity J Virol 1995
16354571 Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions Cell Res 2005
10620603 The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore J Exp Med 2000
8041786 The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells Proc Natl Acad Sci U S A 1994
9582382 Viral protein R regulates docking of the HIV-1 preintegration complex to the nuclear pore complex J Biol Chem 1998
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