HIV type 1 Nef increases the association of T cell receptor (TCR)-signaling molecules with T cell rafts and promotes activation-induced raft fusion.

Abstract:

:HIV-1 Nef (Nef) is a myristoylated protein that contributes to HIV disease pathogenesis. Nef has a modulatory effect on T cell receptor (TCR) signaling, resulting in up-regulation of interleukin-2 (IL-2) production in stimulated T cells. Recent studies have shown that efficient TCR signaling requires enhanced association of TCR-signaling molecules with plasma membrane microdomains (lipid rafts) and fusion of rafts into larger structures. We utilized Jurkat T cell lines expressing wild-type Nef (Nef(wt)) and a myristoylation-deficient form of Nef (Nef(G)2(A)), from an inducible promoter, to determine the effects of Nef on the association of TCR-signaling molecules with rafts in nonstimulated T cells. In addition, the effect of Nef on raft size, before and after TCR activation by CD3 cross-linking, was also examined. Following induction, Nef(wt) was associated with both rafts and nonrafts, while Nef(G)2(A) was almost exclusively cytosolic. Induction of Nef(wt), but not Nef(G)2(A), coincided with an increased association of the src family tyrosine kinase, Lck, and TCRzeta with rafts, but not with nonrafts. Further, rafts were found to be significantly larger in CD3-activated T cells in the presence of Nef(wt) when compared to nonexpressing cells. We propose that myristoylated, raft-localized Nef primes resting T cells for activation by increasing the levels of signaling molecules within rafts, and that TCR activation is enhanced by the capacity of Nef to promote raft fusion.

authors

Djordjevic JT,Schibeci SD,Stewart GJ,Williamson P

doi

10.1089/088922204323087804

subject

Has Abstract

pub_date

2004-05-01 00:00:00

pages

547-55

issue

5

eissn

0889-2229

issn

1931-8405

journal_volume

20

pub_type

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