Analysis of apoptosis induced by HIV-1 Vpr and examination of the possible role of the hHR23A protein.
The HIV-1 Vpr protein induces apoptosis of cells, the mechanism of which is unknown. To clarify how this function may be related to other Vpr functions, we simultaneously assessed the effects of multiple point mutations upon various Vpr properties. Our data suggest that induction of arrest by Vpr may be unnecessary for induction of apoptosis. This is exemplified by a C-terminal mutant, R80A, that does not arrest cells, yet induces low but significant levels of apoptosis. We also show that mutation of Vpr at both of its nuclear localization sequences (within its alpha-helices and the overlapping leucine zipper-like domain) does not affect induction of either apoptosis or cell cycle arrest. This indicates that neither sequence is essential for these two functions of Vpr. It further suggests that multimerization of Vpr, which maps to residues 60 and 67 within the leucine-rich region, is unnecessary for initiation of apoptosis and arrest. We previously found that the Vpr-binding protein, hHR23A, can partially alleviate induction of arrest. We now show that overexpression of hHR23A itself causes apoptosis of cells. Mutation of its C-terminal UBA( 2 ) domain that is responsible for binding Vpr disrupts the apoptotic effect. This suggests that Vpr may induce apoptosis through a pathway involving hHR23A.
Gaynor
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EM
UCLA AIDS Institute, University of California at Los Angeles School of Medicine, Los Angeles, California 90095-1678, USA.
Chen
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D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016336:Gene Products, vpr / Q000378:metabolism*; D016334:Genes, vpr; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D013997:Time Factors; D014162:Transfection; D054325:vpr Gene Products, Human Immunodeficiency Virus
D004268:DNA-Binding Proteins; D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus; C086985:RAD23A protein, human; D045643:DNA Repair Enzymes