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Interactions of Vpr with host cellular proteins

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.

from REACTOME source record: R-HSA-176033
Type: pathway
Taxonomic scope
organism-specific biosystem
Homo sapiens

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