Human immunodeficiency virus type 1 Vpr-mediated G(2) cell cycle arrest: Vpr interferes with cell cycle signaling cascades by interacting with the B subunit of serine/threonine protein phosphatase 2A.
The Vpr protein of primate lentiviruses arrests cell cycling at the G(2)/M phase through an inactivation of cyclin B-p34(cdc2) and its upstream regulator cdc25. We provide here biochemical and functional evidence demonstrating that human immunodeficiency virus type 1 (HIV-1) Vpr mediates G(2) arrest by forming a complex with protein phosphatase 2A (PP2A), an upstream regulator of cdc25. Vpr associates with PP2A through a specific interaction with the B55 regulatory subunit. This interaction is necessary but not sufficient for G(2) arrest. Interestingly, we found that Vpr association with B55-containing PP2A targets the enzymatic complex to the nucleus and, importantly, enhances the recruitment and dephosphorylation of the cdc25 substrate. Our data suggest that Vpr mediates G(2) arrest by enhancing the nuclear import of PP2A and by positively modulating its catalytic activity towards active phosphorylated nuclear cdc25.
Laboratoire de Rétrovirologie Humaine, Département de microbiologie et immunologie, Faculté de médecine, Université de Montréal, Montreal, Quebec, Canada H3C 3J7.
M
M
Hrimech
X J
XJ
Yao
P E
PE
Branton
E A
EA
Cohen
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D019556:COS Cells; D002451:Cell Compartmentation; D018797:Cell Cycle Proteins / Q000378:metabolism; D016195:G2 Phase; D016336:Gene Products, vpr / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011485:Protein Binding; D054648:Protein Phosphatase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D020687:cdc25 Phosphatases / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus
D018797:Cell Cycle Proteins; D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C517009:CDC25C protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D020687:cdc25 Phosphatases