HIV-1 Nef promotes survival of myeloid cells by a Stat3-dependent pathway.
Human immunodeficiency virus Nef is a small myristylated protein that plays a critical role in AIDS progression. Nef binds with high affinity to the SH3 domain of the myeloid-restricted tyrosine kinase Hck in vitro, identifying this Src-related kinase as a possible cellular target for Nef in macrophages. Here we show that Nef activates endogenous Hck in the granulocyte-macrophage colony-stimulating factor-dependent myeloid cell line, TF-1. Unexpectedly, Nef induced cytokine-independent TF-1 cell outgrowth and constitutive activation of the Stat3 transcription factor. Induction of survival required the Nef SH3 binding and membrane-targeting motifs and was blocked by dominant-negative Stat3 mutants. Nef also stimulated Stat3 activation in primary human macrophages, providing evidence for Stat3 as a Nef effector in a target cell for human immunodeficiency virus.
Briggs
S D
SD
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Scholtz
B
B
Jacque
J M
JM
Swingler
S
S
Stevenson
M
M
Smithgall
T E
TE
D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D015693:Gene Products, nef / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D008264:Macrophages / Q000201:enzymology; D019814:Myristic Acid / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D054311:nef Gene Products, Human Immunodeficiency Virus; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism
D004268:DNA-Binding Proteins; D015693:Gene Products, nef; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D054311:nef Gene Products, Human Immunodeficiency Virus; D019814:Myristic Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019061:src-Family Kinases