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A more recent version of this article appeared on September 1, 2007
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Submitted on March 8, 2007
Revised on May 24, 2007
Accepted on June 11, 2007
*University of Cambridge, Cambridge Institute for Medical Research, Cambridge CB2 0XY, United Kingdom; Institut Curie, 75005 Paris, France
Monitoring Editor: Sandra Lemmon
MHC class I is down-regulated from the surface of HIV-1-infected cells by Nef, a virally encoded protein that is thought to reroute MHC-I to the TGN in a PACS-1, AP-1, and clathrin-dependent manner. More recently, an alternative model has been proposed, in which Nef uses AP-1 to direct MHC-I to endosomes and lysosomes. Here we show that knocking down either AP-1 or clathrin with siRNA inhibits the down-regulation of HLA-A2 (an MHC-I isotype) by Nef in HeLa cells. However, knocking down PACS-1 has no effect, not only on Nef-induced down-regulation of HLA-A2, but also on the localization of other proteins containing acidic cluster motifs. Surprisingly, knocking down AP-2 actually enhances Nef activity. ImmunoEM labeling of Nef-expressing cells indicates that HLA-A2 is rerouted not to the TGN, but to endosomes. In AP-2-depleted cells, more of the HLA-A2 localizes to the inner vesicles of multivesicular bodies. We propose that depleting AP-2 potentiates Nef activity by altering the membrane composition and dynamics of endosomes and causing increased delivery of HLA-A2 to a pre-lysosomal compartment.
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