QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: E07-03-0218v1 18/9/3351    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lubben, N. B. Articles by Robinson, M. S. Search for Related Content PubMed PubMed Citation Articles by Lubben, N. B. Articles by Robinson, M. S.

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.

This article has been cited by other articles:

				H. Toussaint, F.-X. Gobert, M. Schindler, C. Banning, P. Kozik, M. Jouve, F. Kirchhoff, and P. Benaroch Human Immunodeficiency Virus Type 1 Nef Expression Prevents AP-2-Mediated Internalization of the Major Histocompatibility Complex Class II-Associated Invariant Chain J. Virol., September 1, 2008; 82(17): 8373 - 8382. [Abstract] [Full Text] [PDF]

				J. Han, Y. Wang, S. Wang, and C. Chi Interaction of Mint3 with Furin regulates the localization of Furin in the trans-Golgi network J. Cell Sci., July 1, 2008; 121(13): 2217 - 2223. [Abstract] [Full Text] [PDF]

				N. Myhill, E. M. Lynes, J. A. Nanji, A. D. Blagoveshchenskaya, H. Fei, K. Carmine Simmen, T. J. Cooper, G. Thomas, and T. Simmen The Subcellular Distribution of Calnexin Is Mediated by PACS-2 Mol. Biol. Cell, July 1, 2008; 19(7): 2777 - 2788. [Abstract] [Full Text] [PDF]

				R. Ishizaki, H.-W. Shin, H. Mitsuhashi, and K. Nakayama Redundant Roles of BIG2 and BIG1, Guanine-Nucleotide Exchange Factors for ADP-Ribosylation Factors in Membrane Traffic between the trans-Golgi Network and Endosomes Mol. Biol. Cell, June 1, 2008; 19(6): 2650 - 2660. [Abstract] [Full Text] [PDF]

				K. Haberg, R. Lundmark, and S. R. Carlsson SNX18 is an SNX9 paralog that acts as a membrane tubulator in AP-1-positive endosomal trafficking J. Cell Sci., May 1, 2008; 121(9): 1495 - 1505. [Abstract] [Full Text] [PDF]

				K. M. Atkins, L. Thomas, R. T. Youker, M. J. Harriff, F. Pissani, H. You, and G. Thomas HIV-1 Nef Binds PACS-2 to Assemble a Multikinase Cascade That Triggers Major Histocompatibility Complex Class I (MHC-I) Down-regulation: ANALYSIS USING SHORT INTERFERING RNA AND KNOCK-OUT MICE J. Biol. Chem., April 25, 2008; 283(17): 11772 - 11784. [Abstract] [Full Text] [PDF]

				E. R. Wonderlich, M. Williams, and K. L. Collins The Tyrosine Binding Pocket in the Adaptor Protein 1 (AP-1) {micro}1 Subunit Is Necessary for Nef to Recruit AP-1 to the Major Histocompatibility Complex Class I Cytoplasmic Tail J. Biol. Chem., February 8, 2008; 283(6): 3011 - 3022. [Abstract] [Full Text] [PDF]

				O. W. Lindwasser, W. J. Smith, R. Chaudhuri, P. Yang, J. H. Hurley, and J. S. Bonifacino A Diacidic Motif in Human Immunodeficiency Virus Type 1 Nef Is a Novel Determinant of Binding to AP-2 J. Virol., February 1, 2008; 82(3): 1166 - 1174. [Abstract] [Full Text] [PDF]

				C. M. Noviello, S. Benichou, and J. C. Guatelli Cooperative Binding of the Class I Major Histocompatibility Complex Cytoplasmic Domain and Human Immunodeficiency Virus Type 1 Nef to the Endosomal AP-1 Complex via Its {micro} Subunit J. Virol., February 1, 2008; 82(3): 1249 - 1258. [Abstract] [Full Text] [PDF]