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J Biol Chem, Vol. 273, Issue 52, 35153-35160, December 25, 1998

A Novel Mechanism of CD4 Down-modulation Induced by Monosialoganglioside GM3
INVOLVEMENT OF SERINE PHOSPHORYLATION AND PROTEIN KINASE C  TRANSLOCATION

Tina Garofalo, Maurizio Sorice, Roberta Misasi, Benedetta Cinque^§, Maria Giammatteo^¶, Giuseppe M. Pontieri, Maria Grazia Cifone^§, and Antonio Pavan^§

From the ^§ Dipartimento di Medicina Sperimentale, Università di L'Aquila, Via Vetoio Coppito 2, L'Aquila 67100, Italy,  Dipartimento di Medicina Sperimentale e Patologia, Università di Roma "La Sapienza," Viale Regina Elena 324, Roma 00161, Italy, and ^¶ Centro di Microscopia, Università di L'Aquila, Via Monteluco di Roio, L'Aquila 67100, Italy

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  and  (more evidently than  and ) 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.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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