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J. Biol. Chem., Vol. 275, Issue 22, 16513-16517, June 2, 2000
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From the Nef is a lentiviral protein involved in
pathogenesis of AIDS, but its molecular mechanisms of action remain
incompletely understood. Here we report a novel effect of Nef on
lymphocyte signaling, which is mediated via a T cell receptor
(TCR)-independent contribution of Nef to induction of nuclear factor of
activated T cells (NFAT), a transcription factor that plays a central
role in coordinating T cell activation. Expression of Nef did not
significantly alter the basal level of NFAT activity in Jurkat cells
nor the increased activity following T cell receptor stimulation by
anti-CD3 or anti-CD3 + anti-CD28. We also mimicked NFAT induction by
TCR triggering by simultaneous activation of the Ras and calcium
signaling pathways with phorbol 12-myristate 13-acetate and ionomycin,
respectively. Strikingly, whereas activation of either of these
pathways individually did not induce NFAT activity in control cells, in
Nef-expressing cells phorbol 12-myristate 13-acetate treatment alone
resulted in a 100-fold increase in NFAT-directed gene expression.
Experiments with different dominant negative mutant signaling proteins,
inhibitory chemicals, and Lck-deficient Jurkat cells revealed that this
effect was mediated via activation of calcineurin by Nef-induced
changes in calcium metabolism, but was independent of TCR-associated
signaling events. This ability of Nef to substitute for triggering of
the calcium pathway in induction of NFAT could promote activation of
human immunodeficiency virus (HIV)-infected T cells in response to
stimuli mediated via TCR or other cell surface receptors under conditions when activation of Ras rather than calcium signaling would
otherwise predominate.
Synergistic Activation of NFAT by HIV-1 Nef and the Ras/MAPK
Pathway*
,§, and¶
Institute of Medical Technology, University
of Tampere, P. O. Box 607, FIN-33101 and the ¶ Department of
Clinical Chemistry, Tampere University Hospital, P. O. Box 2000,
FIN-33521, Tampere, Finland
*
This work was supported by Grant SA152304 (to K. S.)
from the Academy of Finland and the Medical Research Fund of Tampere University Hospital.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Inst. of Medical
Technology, University of Tampere, Finn-Medi II Bldg., Rm. 4-137; Lenkkeilijankatu 8, FIN-33520, Tampere, Finland. Tel.: 358-3-215-7029; Fax: 358-3-215-8597; E-mail: kalle.saksela@uta.fi.
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