Zhong G, Castellino F, Romagnoli P, Germain R N
Lymphocyte Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892, USA.
J Exp Med. 1996 Nov 1;184(5):2061-6. doi: 10.1084/jem.184.5.2061.
Invariant chain (Ii) associates with newly synthesized class II molecules in the endoplasmic reticulum (ER), an interaction that has been shown to interfere with peptide binding to class II molecules. The class II-associated invariant chain peptide (CLIP) region (residues 81-104) of Ii is believed to mediate this inhibition by engaging the binding domain of class II like an antigenic peptide. Together, these findings have given rise to a model in which CLIP association with the class II groove acts to prevent inappropriate presentation of peptides imported into the ER for association with major histocompatibility complex class I molecules. However, the properties of class II molecules synthesized by cells lacking coexpressed Ii are at least superficially inconsistent with this paradigm in that they do not show clear evidence of peptide acquisition. At the same time, we have previously shown the shortest form of Ii still containing CLIP to play an essential role in regulation of early class II molecule assembly and transport in the secretory pathway. Using covalent peptide technology, we now show that occupancy of the class II binding site in the ER regulates class II trafficking to the Golgi complex, an event that is the locus of the major defect in cells of Ii-deficient mice. These data argue that CLIP occupies the class II binding site, not to prevent interaction with short peptides meant for class I, but rather to maintain the structural integrity of class II molecules that are labile without engaged binding regions, and that would also associate with intact proteins in the ER if left unoccupied. By these means, CLIP occupancy of the class II binding site promotes effective export of useful class II molecules for endocytic peptide acquisition.
恒定链（Ii）在内质网（ER）中与新合成的II类分子结合，这种相互作用已被证明会干扰肽与II类分子的结合。Ii的II类相关恒定链肽（CLIP）区域（第81 - 104位氨基酸残基）被认为通过像抗原肽一样占据II类分子的结合结构域来介导这种抑制作用。这些发现共同形成了一个模型，即CLIP与II类分子凹槽的结合作用是为了防止导入内质网与主要组织相容性复合体I类分子结合的肽被不恰当地呈递。然而，缺乏共表达Ii的细胞合成的II类分子的特性至少在表面上与该范式不一致，因为它们没有显示出明显的肽获取证据。同时，我们之前已经表明，仍然含有CLIP的最短形式的Ii在调节分泌途径中早期II类分子组装和运输方面起着至关重要的作用。利用共价肽技术，我们现在表明内质网中II类分子结合位点的占据情况调节II类分子向高尔基体复合体的运输，这一事件是Ii缺陷小鼠细胞中主要缺陷的发生位点。这些数据表明，CLIP占据II类分子结合位点，不是为了防止与用于I类分子的短肽相互作用，而是为了维持II类分子的结构完整性，这些II类分子如果没有结合区域参与会不稳定，并且如果不被占据还会在内质网中与完整蛋白质结合。通过这些方式，CLIP对II类分子结合位点的占据促进了用于内吞肽获取的有用II类分子的有效输出。
