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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Involvement of clathrin and AP-2 in the trafficking of MHC class Ⅱ molecules to antigen-processing compartments
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Involvement of clathrin and AP-2 in the trafficking of MHC class Ⅱ molecules to antigen-processing compartments

机译：网格蛋白和AP-2参与MHCⅡ类分子向抗原加工区室的运输

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摘要

Major histocompatibility complex class Ⅱ (MHC-Ⅱ) molecules are composed of two polymorphic chains, α and β, which assemble with an invariant chain, li, in the endoplasmic reticulum. The assembled MHC-Ⅱ complexes are transported to the Golgi complex and then to late endosomes/lysosomes, where li is degraded and αβ dimers 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 li. 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 li expression on the cell surface and a concomitant decrease in li localization to endosomal lysosomal vesicles. In addition, depletion of clathrin or AP-2 delayed the degradation of li and reduced the surface expression of peptide-loaded αβ dimers. 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.
机译：主要的组织相容性复合物Ⅱ类（MHC-Ⅱ）分子由两个多态性链α和β组成，它们在内质网中与不变链li组装在一起。组装的MHC-Ⅱ复合物被转运至高尔基体，然后转运至晚期核糖体/溶酶体，在那里li降解，αβ二聚体结合源自外源抗原的肽。 MHC-Ⅱ分子对这些区室的靶向是由li的胞质域中的两个基于双亮氨酸的信号介导的。这些信号在体外与两种衔接蛋白（AP）复合物AP-1和AP-2结合，这两种复合物是网格蛋白涂层的组成部分，参与囊泡形成和货物分选。这些蛋白质在MHC-Ⅱ分子运输中的生理作用，仍然有待解决。在这里，我们报告使用RNA干扰来检查网格蛋白和四种AP复合物（AP-1，AP-2，AP-3和AP-4）在体内MHC-Ⅱ分子运输中的参与。我们发现，网格蛋白或AP-2的耗竭导致细胞表面上li表达的增加> 10倍，并伴随着li定位于内体溶酶体囊泡的减少。另外，网格蛋白或AP-2的耗竭延迟了li的降解并降低了载有肽的αβ二聚体的表面表达。相反，耗尽AP-1，AP-3或AP-4几乎没有影响。这些发现表明网格蛋白和AP-2参与体内的MHC-Ⅱ分子运输。因为AP-2仅与质膜相关，所以这些结果还表明，大量MHC-Ⅱ分子通过细胞表面运向内体-溶酶体系统。

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