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Vol. 18, Issue 9, 3351-3365, September 2007

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HIV-1 Nef-induced Down-Regulation of MHC Class I Requires AP-1 and Clathrin but Not PACS-1 and Is Impeded by AP-2

Nienke B. Lubben^*, Daniela A. Sahlender^*, Alison M. Motley^*, Paul J. Lehner^*, Philippe Benaroch, and Margaret S. Robinson^*

*University of Cambridge, Cambridge Institute for Medical Research, Cambridge CB2 0XY, United Kingdom; and Institut Curie, 75005 Paris, France

Submitted March 8, 2007; Revised May 24, 2007; Accepted June 11, 2007
Monitoring Editor: Sandra Lemmon

Major histocompatibility complex class I is down-regulated from the surface of human immunodeficiency virus (HIV)-1-infected cells by Nef, a virally encoded protein that is thought to reroute MHC-I to the trans-Golgi network (TGN) in a phosphofurin acidic cluster sorting protein (PACS) 1, adaptor protein (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 small interfering RNA 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. Immuno-electron microscopy 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 prelysosomal compartment.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Margaret S. Robinson (msr12{at}mole.bio.cam.ac.uk).

Abbreviations used: AP, adaptor protein; CCV, clathrin-coated vesicle; CHC, clathrin heavy chain; CPD, carboxypeptidase D; LAMP, lysosome-associated membrane protein; MVB, multivesicular body; PACS, phosphofurin acidic cluster sorting protein.

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