The invariant chain (Ii, also known as CD74) is a multifunctional regulator of adaptive immune responses and is responsible for sorting major histocompatibility complex class I and class II (MHCI and MHCII, respectively) molecules, as well as other Ii-associated molecules, to a specific endosomal pathway. When Ii is expressed, endosomal maturation and proteolytic degradation of proteins are delayed and, in non-antigen presenting cells, the endosomal size increases, but the molecular mechanisms underlying this are not known. We identified that a SNARE, Vti1b, is essential for regulating these Ii-induced effects. Vti1b binds to Ii and is localized at the contact sites of fusing Ii-positive endosomes. Furthermore, truncated Ii lacking the cytoplasmic tail, which is not internalized from the plasma membrane, relocates Vti1b to the plasma membrane. Knockout of Ii in an antigen-presenting cell line was found to speed up endosomal maturation, whereas silencing of Vti1b inhibits the Ii-induced maturation delay. Our results suggest that Ii, by interacting with the SNARE Vti1b in antigen-presenting cells, directs specific Ii-associated SNARE-mediated fusion in the early part of the endosomal pathway that leads to a slower endosomal maturation for efficient antigen processing and MHC antigen loading.

不变链（Ii，也称为 CD74）是适应性免疫反应的多功能调节剂，负责分类主要组织相容性复合物 I 类和 II 类（分别为 MHCI 和 MHCII）分子，以及其他 Ii 相关分子，进入特定的内体途径。当 Ii 表达时，内体成熟和蛋白质的蛋白水解降解被延迟，并且在非抗原呈递细胞中，内体大小增加，但其背后的分子机制尚不清楚。我们发现 SNARE，Vti1b，对于调节这些 Ii 诱导的效应至关重要。Vti1b 与 Ii 结合并位于融合 Ii 阳性核内体的接触位点。此外，缺乏细胞质尾部的截短 Ii 不会从质膜内化，将 Vti1b 重新定位到质膜。研究发现，抗原呈递细胞系中 Ii 的敲除可加速内体成熟，而 Vti1b 的沉默可抑制 Ii 诱导的成熟延迟。我们的结果表明，Ii 通过与抗原呈递细胞中的 SNARE Vti1b 相互作用，在内体途径的早期部分指导特异性 Ii 相关的 SNARE 介导的融合，从而导致较慢的内体成熟，从而实现有效的抗原加工和 MHC 抗原加载。