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Vav exchange factor counteracts the HIV‐1 Nef‐mediated decrease of plasma membrane GM1 and NF‐AT activity in T cells
Author(s) -
Tuosto Loretta,
Marinari Barbara,
Andreotti Mauro,
Federico Maurizio,
Piccolella Enza
Publication year - 2003
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.200323682
Subject(s) - microbiology and biotechnology , lipid raft , biology , intracellular , jurkat cells , regulator , t cell receptor , signal transduction , t cell , downregulation and upregulation , ectopic expression , lipid microdomain , membrane , biochemistry , immunology , immune system , gene
Abstract Several findings support the importance of GM1‐enriched lipid microdomains of plasma membrane and of Vav, an essential regulator of actin cytoskeletal rearrangement, in the regulation of T cell activation. Moreover, a functional link among lipid microdomains, Vav and the HIV product Nef has been described. These observations suggest that Nef can modify plasma membrane GM1, affecting the behavior of HIV‐infected cells towards antigen recognition and Vav towards counteracting such an effect. We observed that Nef expression, either following viral infection or ectopic expression, significantly decreased the level of plasma membrane GM1 in unstimulated T cells. This down‐regulation was associated with the inhibition of NF‐AT activation, but not with NF‐κB activation inducedby TCR engagement. Dissecting the signaling pathway that regulates NF‐AT activation, we found that Nef inhibited exclusively the Ca 2+ /calcineurin cascade, whereas the JNK cascade and AP‐1 transcriptional activity were not affected. Our evidence that Vav overexpression counteracted both the Nef‐induced decrease of GM1 expression and the inhibition of NF‐AT activity, suggests a novel mechanism by which Nef may interfere with TCR‐mediated activation through the modulation of intracellular trafficking and clustering of GM1‐enriched microdomains at the cell surface.