Abstract
In this report the molecular mechanism(s) involved in the rapid and selective endocytosis of cell surface glycoprotein CD4 induced by exogenous monosialoganglioside GM3 in human peripheral blood lymphocytes have been investigated. Inhibition of the GM3-induced CD4 down-modulation was observed in the presence of specific protein kinase C (PKC) inhibitors. Scanning confocal microscopy revealed the translocation and clustering on the cell surface of PKC isozymes delta and theta (more evidently than alpha and beta) after GM3 treatment, suggesting the involvement of these isozymes in the ganglioside-induced CD4 down-modulation. Exogenous GM3 induced phosphorylation of CD4 molecule, which then dissociated from p56(lck), as early as after 5 min. Moreover, addition of GM3 resulted in a rapid (1 min) cytosolic phospholipase A2 activation with consequent arachidonic acid release, whereas no phosphatidylinositol-phospholipase C activity was observed. Both PKC translocation and CD4 down-modulation were blocked by the trifluoromethylketone analog of arachidonic acid, a selective inhibitor of cytosolic phospholipase A2 and by mitogen-activated protein kinase inhibitor PD98059. Taken together, these findings strongly suggest that GM3 may trigger a novel mechanism of modulation of the CD4 surface expression through the activation of enzyme(s) involved in the regulation of cellular functions.
Highlights
In this report the molecular mechanism(s) involved in the rapid and selective endocytosis of cell surface glycoprotein CD4 induced by exogenous monosialoganglioside GM3 in human peripheral blood lymphocytes have been investigated
We previously reported that addition of exogenous GM3 induces down-modulation of CD4 molecules in human T lymphocytes, with a CD4 redistribution on the cell surface, and clustering and internalization via endocytic pits and vesicles, followed by intracellular degradation [22]
protein kinase C (PKC) Involvement in GM3-induced CD4 Endocytosis—In agreement with our previous results [22], incubation of peripheral blood lymphocytes (PBLs) with GM3 was followed by a significant decrease of CD4 staining on both epitopes recognized by DAKO-T4 (Fig. 1, A and B) and OKT4
Summary
In this report the molecular mechanism(s) involved in the rapid and selective endocytosis of cell surface glycoprotein CD4 induced by exogenous monosialoganglioside GM3 in human peripheral blood lymphocytes have been investigated. Both PKC translocation and CD4 down-modulation were blocked by the trifluoromethylketone analog of arachidonic acid, a selective inhibitor of cytosolic phospholipase A2 and by mitogen-activated protein kinase inhibitor PD98059 Taken together, these findings strongly suggest that GM3 may trigger a novel mechanism of modulation of the CD4 surface expression through the activation of enzyme(s) involved in the regulation of cellular functions. CD4 down-regulation on T cell plasma membrane is a well known molecular event triggered by different stimuli, which, through activation of PKC, induce the phosphorylation of serine residues in the cytoplasmic tail of CD4 molecule and, the dissociation of the CD41⁄7p56lck complex [19]. The possible mechanisms underlying these events have been analyzed
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