Institute of Molecular Biology gGmbH (IMB), Ackermannweg 4, D-55128 Mainz, Germany.
Institut Jacques Monod, UMR 7592 Centre National de la Recherche Scientifique/Université Paris-Diderot, Sorbonne Paris Cité, 75205 Paris Cedex 13, France.
J Cell Sci. 2020 May 27;133(10):jcs244566. doi: 10.1242/jcs.244566.
Polyubiquitin chains linked via lysine (K) 63 play an important role in endocytosis and membrane trafficking. Their primary source is the ubiquitin protein ligase (E3) Rsp5/NEDD4, which acts as a key regulator of membrane protein sorting. The heterodimeric ubiquitin-conjugating enzyme (E2), Ubc13-Mms2, catalyses K63-specific polyubiquitylation in genome maintenance and inflammatory signalling. In budding yeast, the only E3 proteins known to cooperate with Ubc13-Mms2 so far is a nuclear RING finger protein, Rad5, involved in the replication of damaged DNA. Here, we report a contribution of Ubc13-Mms2 to the sorting of membrane proteins to the yeast vacuole via the multivesicular body (MVB) pathway. In this context, Ubc13-Mms2 cooperates with Pib1, a FYVE-RING finger protein associated with internal membranes. Moreover, we identified a family of membrane-associated FYVE-(type)-RING finger proteins as cognate E3 proteins for Ubc13-Mms2 in several species, and genetic analysis indicates that the contribution of Ubc13-Mms2 to membrane trafficking in budding yeast goes beyond its cooperation with Pib1. Thus, our results widely implicate Ubc13-Mms2 as an Rsp5-independent source of K63-linked polyubiquitin chains in the regulation of membrane protein sorting.This article has an associated First Person interview with the first author of the paper.
多聚泛素链通过赖氨酸（K）63 连接在细胞内吞和膜运输中发挥重要作用。它们的主要来源是泛素蛋白连接酶（E3）Rsp5/NEDD4，它是膜蛋白分选的关键调节剂。异源二聚泛素结合酶（E2）Ubc13-Mms2 催化基因组维持和炎症信号转导中的 K63 特异性多泛素化。在 budding yeast 中，迄今为止，已知与 Ubc13-Mms2 合作的唯一 E3 蛋白是一种核 RING 指蛋白 Rad5，它参与受损 DNA 的复制。在这里，我们报告了 Ubc13-Mms2 通过多泡体（MVB）途径对膜蛋白分选到酵母液泡中的贡献。在这种情况下，Ubc13-Mms2 与 Pib1 合作，Pib1 是一种与内部膜相关的 FYVE-RING 指蛋白。此外，我们鉴定了一系列膜相关 FYVE-（类型）-RING 指蛋白作为 Ubc13-Mms2 在几个物种中的同源 E3 蛋白，遗传分析表明 Ubc13-Mms2 对 budding yeast 中膜运输的贡献超出了其与 Pib1 的合作。因此，我们的结果广泛表明 Ubc13-Mms2 是调节膜蛋白分选的 K63 连接多泛素链的 Rsp5 非依赖性来源。本文有一篇与该论文第一作者的第一人称访谈。
