Evidence that binding site occupancy is necessary and sufficient for effective major histocompatibility complex (MHC) class II transport through the secretory pathway redefines the primary function of class II-associated invariant chain peptides (CLIP)
Evidence that binding site occupancy is necessary and sufficient for effective major histocompatibility complex (MHC) class II transport through the secretory pathway redefines the primary function of class II-associated invariant chain peptides (CLIP)
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DOI：
10.1084/jem.184.5.2061
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发表时间：
1996-11-01
影响因子：
15.3
通讯作者：
Germain, RN
中科院分区：
文献类型：
--
作者：
Zhong, GM;Castellino, F;Germain, RN
不变链（Ii）与内质网（ER）中新合成的II类分子相关联，这种相互作用已显示干扰肽与II类分子的结合。据信Ii的II类相关不变链肽（CLIP）区（残基81-104）通过接合II类的结合结构域（如抗原肽）来介导这种抑制。总之，这些发现产生了一个模型，其中CLIP与II类沟的关联起作用，以防止输入到ER中的肽与主要组织相容性复合体I类分子的关联的不适当呈递。然而，由缺乏共表达Ii的细胞合成的II类分子的性质至少在表面上与这种范式不一致，因为它们没有显示出肽获得的明确证据。与此同时，我们以前已经表明，Ii的最短形式仍然含有CLIP在早期II类分子组装和运输的分泌途径中发挥重要作用。使用共价肽技术，我们现在表明，在ER中的II类结合位点的占用调节II类运输到高尔基复合体，一个事件，这是在细胞中的主要缺陷的Ii缺陷小鼠的轨迹。这些数据表明，CLIP占据II类结合位点，不是为了防止与I类短肽的相互作用，而是为了保持II类分子的结构完整性，这些分子在没有结合区域的情况下是不稳定的，并且如果未被占据，也会与ER中的完整蛋白质相关联。通过这些方法，CLIP对II类结合位点的占据促进了有用的II类分子的有效输出，用于内吞肽的获取。
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.