Elliott E A, Drake J R, Amigorena S, Elsemore J, Webster P, Mellman I, Flavell R A
Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510.
J Exp Med. 1994 Feb 1;179(2):681-94. doi: 10.1084/jem.179.2.681.
The major histocompatibility complex (MHC) class II-associated invariant chain (Ii) is thought to act as a chaperone that assists class II during folding, assembly, and transport. To define more precisely the role of Ii chain in regulating class II function, we have investigated in detail the biosynthesis, transport, and intracellular distribution of class II molecules in splenocytes from mice bearing a deletion of the Ii gene. As observed previously, the absence of Ii chain caused significant reduction in both class II-restricted antigen presentation and expression of class II molecules at the cell surface because of the intracellular accumulation of alpha and beta chains. Whereas much of the newly synthesized MHC molecules enter a high molecular weight aggregate characteristic of misfolded proteins, most of the alpha and beta chains form dimers and acquire epitopes characteristic of properly folded complexes. Although the complexes do not bind endogenously processed peptides, class II molecules that reach the surface are competent to bind peptides added to the medium, further demonstrating that at least some of the complexes fold properly. Similar to misfolded proteins, however, the alpha and beta chains are poorly terminally glycosylated, suggesting that they fail to reach the Golgi complex. As demonstrated by double label confocal and electron microscope immunocytochemistry, class II molecules were found in a subcompartment of the endoplasmic reticulum and in a population of small nonlysosomal vesicles possibly corresponding to the intermediate compartment or cis-Golgi network. Thus, although alpha and beta chains can fold and form dimers on their own, the absence of Ii chain causes them to be recognized as "misfolded" and retained in the same compartments as bona fide misfolded proteins.
主要组织相容性复合体（MHC）II类相关恒定链（Ii）被认为是一种伴侣蛋白，在折叠、组装和运输过程中协助II类分子。为了更精确地定义Ii链在调节II类分子功能中的作用，我们详细研究了Ii基因缺失小鼠脾细胞中II类分子的生物合成、运输和细胞内分布。如先前观察到的，由于α链和β链在细胞内的积累，Ii链的缺失导致II类分子限制的抗原呈递以及细胞表面II类分子表达显著降低。尽管许多新合成的MHC分子进入了错误折叠蛋白特有的高分子量聚集体，但大多数α链和β链形成二聚体并获得正确折叠复合物特有的表位。虽然这些复合物不结合内源性加工的肽，但到达细胞表面的II类分子能够结合添加到培养基中的肽，这进一步证明至少一些复合物能正确折叠。然而，与错误折叠的蛋白类似，α链和β链的末端糖基化程度很低，表明它们未能到达高尔基体复合体。通过双标记共聚焦和电子显微镜免疫细胞化学证明，在内质网的一个亚区室以及可能对应于中间区室或顺式高尔基体网络的一群小的非溶酶体囊泡中发现了II类分子。因此，尽管α链和β链能够自行折叠并形成二聚体，但Ii链的缺失导致它们被识别为“错误折叠”，并与真正错误折叠的蛋白保留在相同的区室中。
