The interplay between E2 and E3 enzymes regulates the polyubiquitination of substrates in eukaryotes. Among the several RING-domain E3 ligases in humans, many utilize two distinct E2s for polyubiquitination. For example, the cell cycle regulatory E3, human anaphase-promoting complex/cyclosome (APC/C), relies on UBE2C to prime substrates with ubiquitin (Ub) and on UBE2S to extend polyubiquitin chains. However, the potential coordination between these steps in ubiquitin chain formation remains undefined. While numerous studies have unveiled how RING E3s stimulate individual E2s for Ub transfer, here we change perspective to describe a case where the chain-elongating E2 UBE2S feeds back and directly stimulates the E3 APC/C to promote substrate priming and subsequent multiubiquitination by UBE2C. Our work reveals an unexpected model for the mechanisms of RING E3-dependent ubiquitination and for the diverse and complex interrelationship between components of the ubiquitination cascade.

中文翻译：

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泛素链延长酶UBE2S激活RING E3连接酶APC / C，用于底物引发。

E2和E3酶之间的相互作用调节了真核生物中底物的多泛素化作用。在人类的几种RING域E3连接酶中，许多利用两个不同的E2进行多聚泛素化。例如，细胞周期调节因子E3（人类后期促进复合物/环体（APC / C））依赖于UBE2C来用泛素（Ub）引发底物，并依赖UBE2S来延伸多泛素链。然而，在遍在蛋白链形成中这些步骤之间的潜在协调仍然不确定。尽管大量研究揭示了RING E3如何刺激单个E2进行Ub转移，但在此我们改变观点来描述延长链的E2 UBE2S反馈并直接刺激E3 APC / C以促进底物引发和随后的UBE2C多泛素化的情况。