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J. Virol., 12 1997, 9531-9537, Vol 71, No. 12
Copyright © 1997, American Society for Microbiology

Activation of the T-cell receptor signaling pathway by Nef from an aggressive strain of simian immunodeficiency virus

W Luo and BM Peterlin
Department of Medicine, Microbiology and Immunology, Howard Hughes Medical Institute, University of California at San Francisco, 94143- 0703, USA.

The Nef from a highly virulent strain of simian immunodeficiency virus (SIV), SIVpbj14, and a Nef from the traditional strain SIVmac239 bearing the mutation from RQ to YE (YE-Nef) both induce an acute lethal disease in monkeys. The YE mutation and its surrounding sequence resemble the immunoreceptor tyrosine-based activation motif (ITAM), which is present in the cytoplasmic tail of T- and B-cell antigen receptors and mediates signaling during lymphocyte activation. We show here that the ITAM from YE-Nef performs the same function. First, not only does YE-Nef increase the activity of the transcription factor NFAT, which is one of the downstream targets of T-cell activation, but the ITAM from the YE-Nef by itself also activates NFAT. Second, the ITAM from YE-Nef is phosphorylated on tyrosine residues by Lck and associates with ZAP-70, a T-cell-specific tyrosine kinase. The phosphorylation of both conserved tyrosine residues on the ITAM is required for the recruitment of ZAP-70. Finally, Lck is required for the activation of NFAT by YE-Nef. These results demonstrate that YE-Nef contains a functional ITAM and elucidate the molecular mechanisms underlying the pathogenesis of SIVpbj14.


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