HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim.
Depletion of CD4(+) T cells is the hallmark of HIV infection and AIDS progression. In addition to the direct killing of the viral-infected cells, HIV infection also leads to increased apoptosis of predominantly uninfected bystander cells. This is mediated in part through the HIV-1 Tat protein, which is secreted by the infected cells and taken up by uninfected cells. Using an affinity-purification approach, a specific and direct interaction of Tat with tubulin and polymerized microtubules has been detected. This interaction does not affect the secretion and uptake of Tat, but is critical for Tat to induce apoptosis. Tat binds tubulin/microtubules through a four-amino-acid subdomain of its conserved core region, leading to the alteration of microtubule dynamics and activation of a mitochondria-dependent apoptotic pathway. Bim, a pro-apoptotic Bcl-2 relative and a transducer of death signals initiated by perturbation of microtubule dynamics, facilitates the Tat-induced apoptosis. Our findings reveal a strategy by which Tat induces apoptosis by targeting the microtubule network. Thus HIV-1 Tat joins a growing list of pathogen-derived proteins that target the cytoskeleton of host cells.
Chen
Dan
D
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720-3206, USA.
Wang
Michael
M
Zhou
Sharleen
S
Zhou
Qiang
Q
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase; D015696:Gene Products, tat / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; D015696:Gene Products, tat; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; D054322:tat Gene Products, Human Immunodeficiency Virus; D005982:Glutathione Transferase