Ii chain controls the transport of major histocompatibility complex class II molecules to and from lysosomes
Ii chain controls the transport of major histocompatibility complex class II molecules to and from lysosomes
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DOI：
10.1083/jcb.137.1.51
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发表时间：
1997-04-07
影响因子：
7.8
通讯作者：
Mellman, I
中科院分区：
文献类型：
--
作者：
Brachet, V;Raposo, G;Mellman, I
主要组织相容性复合体II类分子是由三个ap二聚体与不变（II）链的三聚体结合而成的非美性复合体。在离开TGN后，Ii链细胞质区域的靶向信号将复合物引导到核内体，在核内体中Ii链被蛋白水解加工和去除，使Ii类分子在到达细胞表面之前结合抗原肽。Ii链解离和肽结合被认为发生在一个或多个与内体（指定CIIV）或溶酶体（指定MIIC）相关的内体后位点。我们现在发现，除了最初将crp二聚体靶向核内体外，Ii链还调节随后Ii类分子的转运。在正常情况下，小鼠a20b细胞将所有新合成的II类I-Ab crp二聚体运输到质膜，几乎没有到达溶酶体隔室。然而，半胱氨酸/丝氨酸蛋白酶抑制剂lepeptin对Ii加工的抑制阻断了向细胞表面的运输，并导致溶酶体中I-A(b)类Ii分子的大量选择性积累。在白细胞介素中，I-A(b)二聚体与10-kD nh2末端Ii链片段（Ii-p10）形成稳定的配合物，Ii-p10通常是Ii链加工的短暂中间体，在去除白细胞介素后，Ii-p10被降解并释放，I-A(b)二聚体结合抗原肽，肽负载二聚体从溶酶体缓慢运输到质膜。我们的研究结果表明，Ii链加工速率或效率的改变可以改变Ii类分子的内体后分选，导致溶酶体样MIIC中α - β二聚体的积累增加。因此，Ii链加工的简单差异可能解释了在不同细胞类型或不同发育阶段的溶酶体室中发现的Ii类数量的高度变化。
Major histocompatibility complex class II molecules are synthesized as a nonameric complex consisting of three ap dimers associated with a trimer of invariant (Ii) chains. After exiting the TGN, a targeting signal in the Ii chain cytoplasmic domain directs the complex to endosomes where Ii chain is proteolytically processed and removed, allowing class II molecules to bind antigenic peptides before reaching the cell surface. Ii chain dissociation and peptide binding are thought to occur in one or more postendosomal sites related either to endosomes (designated CIIV) or to lysosomes (designated MIIC). We now find that in addition to initially targeting crp dimers to endosomes, Ii chain regulates the subsequent transport of class II molecules. Under normal conditions, murine A20 B cells transport all of their newly synthesized class II I-Ab crp dimers to the plasma membrane with little if any reaching lysosomal compartments. Inhibition of Ii processing by the cysteine/serine protease inhibitor leupeptin, however, blocked transport to the cell surface and caused a dramatic but selective accumulation of I-A(b) class II molecules in lysosomes. In leupeptin, I-A(b) dimers formed stable complexes with a 10-kD NH2-terminal Ii chain fragment (Ii-p10), normally a transient intermediate in Ii chain processing, Upon removal of leupeptin, Ii-p10 was degraded and released, I-A(b) dimers bound antigenic peptides, and the peptide-loaded dimers were transported slowly from lysosomes to the plasma membrane, Our results suggest that alterations in the rate or efficiency of Ii chain processing can alter the postendosomal sorting of class II molecules, resulting in the increased accumulation of alpha beta dimers in lysosome-like MIIC. Thus, simple differences in Ii chain processing may account for the highly variable amounts of class II found in lysosomal compartments of different cell types or at different developmental stages.