Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 22, Pages 7910-7915Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0502206102
Keywords
invariant chain; adaptor proteins; endosomes; antigen presentation
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Major histocompatibility complex class II (MHC-II) molecules are composed of two polymorphic chains, alpha and beta, which assemble with an invariant chain, Ii, in the endoplasmic reticulum. The assembled MHC-II complexes are transported to the Golgi complex and then to late endosomes/lysosomes, where Ii is degraded and alpha beta climers bind peptides derived from exogenous antigens. Targeting of MHC-II molecules to these compartments is mediated by two dileucine-based signals in the cytoplasmic domain of Ii. These signals bind in vitro to two adaptor protein (AP) complexes, AP-1 and AP-2, which are components of clathrin coats involved in vesicle formation and cargo sorting. The physiological roles of these proteins in MHC-II molecule trafficking, however, remain to be addressed. Here, we report the use of RNA interference to examine the involvement of clathrin and four AP complexes (AP-1, AP-2, AP-3, and AP-4) in MHC-II molecule trafficking in vivo. We found that depletion of clathrin or AP-2 caused > 10-fold increases in Ii expression on the cell surface and a concomitant decrease in Ii localization to endosomal/lysosomal vesicles. in addition, depletion of clathrin or AP-2 delayed the degradation of Ii and reduced the surface expression of peptide-loaded alpha beta dinners. In contrast, depletion of AP-1, AP-3, or AP-4 had little or no effect. These findings demonstrate that clathrin and AP-2 participate in MHC-II molecule trafficking in vivo. Because AP-2 is only associated with the plasma membrane, these results also indicate that a significant pool of MHC-II molecules traffic to the endosomal-lysosomal system by means of the cell surface.
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