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MBC in Press, published online ahead of print June 14, 2006
Mol. Biol. Cell 10.1091/mbc.E06-02-0117

A more recent version of this article appeared on August 1, 2006
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Submitted on February 8, 2006
Revised on May 31, 2006
Accepted on June 1, 2006

The Nef Protein of Human Immunodeficiency Virus is a Broad-Spectrum Modulator of Chemokine Receptor Cell Surface Levels That Acts Independently of Classical Motifs for Receptor Endocytosis and G{alpha}i-Signaling

Nico Michel, Kerstin Ganter, Stephanie Venzke, Julia Bitzegeio, Oliver T. Fackler, and Oliver T. Keppler

Department of Virology, University of Heidelberg, 69120 Heidelberg, Germany

Monitoring Editor: Ralph Isberg

Chemokine receptors (CKRs) are important physiological mediators of immune defense, inflammatory responses, and angiogenesis, and have also been implicated in a number of viral disease processes. Here, we report that the Nef protein of human immunodeficiency virus (HIV) reduces cell surface levels of eight different members of the CC- and CXC-family of CKRs by up to 92%. This broad-range activity required specific elements in HIVSF2 Nef, including the proline-rich motif P73P76P79P82 as well as the acidic cluster motif E66E67E68E69, and Nef expression induced a marked perinuclear accumulation of CKRs. Surprisingly, receptor mutagenesis demonstrated that the cytoplasmic tail of CCR5 and CXCR4, which is critical for basal and ligand-mediated endocytosis, was completely dispensable for this Nef activity. In contrast, triple-mutation of the highly conserved DRY motif in the second intracellular CKR loop abolished the Nef-mediated down-regulation of CXCR4 independently of this motif’s role in CKR binding to heterotrimeric G-proteins and signaling via the G{alpha}i-subunit. Thus, we identify the lentiviral pathogenicity factor Nef as a unique and broad-range modulator of CKR cell surface levels. Nef utilizes a mechanism that is distinct from well-established pathways orchestrating CKR metabolism and offers an interesting tool to study the multifaceted biology of CKRs.

Address correspondence to: Oliver T. Keppler (oliver_keppler{at}med.uni-heidelberg.de)




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