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CD4 Phosphorylation Partially Reverses Nef Down-Regulation of CD4¹

Yong-Jiu Jin^2,*, Xiaoping Zhang, J. Gildade Boursiquot^* and Steven J. Burakoff^*,

^* Skirball Institute of Biomedical Research, Department of Medicine, New York University School of Medicine, New York, NY 10016; and Department of Pharmaceutics, College of Pharmacy, Rutgers University, Piscataway, NJ 08854

HIV Nef down-regulates CD4 from the cell surface in the absence of CD4 phosphorylation, whereas PMA down-regulates CD4 through a phosphorylation-dependent pathway. In this study we show that the down-regulation of CD4 in human Jurkat T cells expressing Nef was nearly complete (95%), whereas that induced by PMA was partial (40%). Unexpectedly, treating T cells expressing Nef with PMA restored the surface CD4 up to 35% of the steady state level. Both mutating the phosphorylation sites in the CD4 cytoplasmic tail (Ser⁴⁰⁸ and Ser⁴¹⁵) and the use of a protein kinase C inhibitor, bisindolylmaleimide1, abolished the restoration of surface CD4, suggesting that the restoration required CD4 phosphorylation. CD4 and Nef could be cross-linked by a chemical cross-linker, 3,3-dithiobis[sulfosuccinimidyl-propionate], in control T cell membranes, but not in PMA-treated T cell membrane, suggesting that CD4 and Nef interacted with each other in T cells, and the phosphorylation disrupted the CD4-Nef interaction. We propose that this dissociation switches CD4 internalization from the Nef-mediated, nearly complete down-regulation to a phosphorylation-dependent, partial down-regulation, resulting in a net gain of CD4 on the T cell surface.

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