Tetraspan cargo adaptors usher GPI-anchored proteins into multivesicular bodies

Ubiquitinated membrane proteins are sorted into intralumenal endosomal vesicles on their way for degradation in lysosomes. Here we summarize the discovery of the Cos proteins, which work to organize and segregate ubiquitinated cargo prior to its incorporation into intralumenal vesicles of the multivesicular body (MVB). Importantly, cargoes such as GPI-anchored proteins (GPI-APs) that cannot undergo ubiquitination, rely entirely on Cos proteins for sorting into intralumenal vesicles using the same pathway that depends on ESCRTs and ubiquitin ligases that typical polytopic membrane proteins do. Here we show Cos proteins provide functions as not only adaptor proteins for ubiquitin ligases, but also as cargo carriers that can physically usher a variety of other proteins into the MVB pathway. We then discuss the significance of this new sorting model and the broader implications for this cargo adaptor mechanism, whereby yeast Cos proteins, and their likely animal analogs, provide a ubiquitin sorting signal in <i>trans</i> to enable sorting of a membrane protein network into intralumenal vesicles.

泛素化膜蛋白在前往溶酶体降解的途中，会被分选进入腔内内体囊泡。本文概述了Cos蛋白（Cos proteins）的发现历程，这类蛋白可在泛素化货物被整合至多泡体（multivesicular body, MVB）的腔内囊泡之前，对其进行组织与分选。值得注意的是，无法发生泛素化修饰的糖基磷脂酰肌醇锚定蛋白（GPI-anchored proteins, GPI-APs）等货物，完全依赖Cos蛋白，通过典型多跨膜膜蛋白所使用的、依赖内体分选转运复合体（ESCRTs）与泛素连接酶的通路，完成腔内囊泡的分选过程。本研究证实，Cos蛋白不仅可作为泛素连接酶的衔接蛋白，还可作为货物载体，通过物理作用将多种其他蛋白引入多泡体通路。随后本文讨论了这一新分选模型的意义，以及该货物衔接机制的更广泛研究价值，其中酵母Cos蛋白及其潜在的动物同源物，可通过反式（trans）提供泛素分选信号，从而介导膜蛋白网络被分选进入腔内内体囊泡。