Gelsolin segment 5 inhibits HIV-induced T-cell apoptosis via Vpr-binding to VDAC.
Viral protein R (Vpr) from the human immunodeficiency virus induces cell cycle arrest in proliferating cells, stimulates virus transcription, and regulates activation and apoptosis of infected T-lymphocytes. We report that Jurkat cells overexpressing full-length gelsolin show resistance to Vpr-induced T-cell apoptosis with abrogation of mitochondrial membrane potential loss and the release of cytochrome c. Co-immunoprecipitation assays in HEK293T cells demonstrated that overexpression of full-length or segment 5 (G5) but not G5-deleted gelsolin (DeltaG5) bound to the voltage-dependent anion channel (VDAC), and that the G5 subunit can inhibit HIV-1-Vpr-binding to VDAC. We also confirmed that full-length gelsolin has the same effect in Jurkat cells. Clonogenic analysis showed that transfection of G5 but not DeltaG5 cDNA protects Jurkat T cells from HIV-Vpr-Tet induced T-cell apoptosis and promoted cell survival, as did full-length gelsolin. These results suggest that the gelsolin G5 domain inhibits HIV-Vpr-induced T-cell apoptosis by blocking the interaction between Vpr and VDAC, and might be used as a protective treatment against HIV-Vpr-induced T-cell apoptosis.
Qiao
Hongjiang
H
Department of Dermatology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan. qiao@igm.hokudai.ac.jp
McMillan
James R
JR
D017209:Apoptosis; D001483:Base Sequence; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D018260:Gelsolin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016336:Gene Products, vpr / Q000502:physiology*; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D019169:Jurkat Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology* / Q000502:physiology / Q000821:virology*; D014162:Transfection; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000502:physiology*; D054325:vpr Gene Products, Human Immunodeficiency Virus
D018076:DNA, Complementary; D018260:Gelsolin; D016336:Gene Products, vpr; D010446:Peptide Fragments; D011994:Recombinant Proteins; C494762:VDAC1 protein, human; D054325:vpr Gene Products, Human Immunodeficiency Virus; D050995:Voltage-Dependent Anion Channel 1