Pérez Berrocal David A, Witting Katharina F, Ovaa Huib, Mulder Monique P C
Department of Cell and Chemical Biology, Chemical Immunology, Leiden University Medical Center, Oncode Institute, Leiden, Netherlands.
Front Chem. 2020 Jan 22;7:931. doi: 10.3389/fchem.2019.00931. eCollection 2019.
The Ubiquitin CODE constitutes a unique post-translational modification language relying on the covalent attachment of Ubiquitin (Ub) to substrates, with Ub serving as the minimum entity to generate a message that is translated into different cellular pathways. The creation of this message is brought about by the dedicated action of writers, erasers, and readers of the Ubiquitin CODE. This CODE is greatly expanded through the generation of polyUb chains of different architectures on substrates thus regulating their fate. Through additional post-translational modification by Ub-like proteins (UbL), hybrid Ub/UbL chains, which either alter the originally encrypted message or encode a completely new one, are formed. Hybrid Ub/UbL chains are generated under both stress or physiological conditions and seem to confer improved specificity and affinity toward their cognate receptors. In such a manner, their formation must play a specific, yet still undefined role in cellular signaling and thus understanding the UbCODE message is crucial. Here, we discuss the evidence for the existence of hybrid Ub/UbL chains in addition to the current understanding of its biology. The modification of Ub by another UbL complicates the deciphering of the spatial and temporal order of events warranting the development of a hybrid chain toolbox. We discuss this unmet need and expand upon the creation of tailored tools adapted from our previously established toolkit for the Ubiquitin Proteasome System to specifically target these hybrid Ub/UbL chains.
泛素密码构成了一种独特的翻译后修饰语言，它依赖于泛素（Ub）与底物的共价连接，其中Ub作为产生一种被转化为不同细胞通路的信息的最小实体。这种信息的产生是由泛素密码的写入器、擦除器和读取器的专门作用实现的。通过在底物上生成不同结构的多聚泛素链，这种密码得到了极大的扩展，从而调节它们的命运。通过类泛素蛋白（UbL）进行额外的翻译后修饰，形成了杂合泛素/UbL链，它们要么改变最初加密的信息，要么编码一个全新的信息。杂合泛素/UbL链在应激或生理条件下都会产生，似乎对其同源受体具有更高的特异性和亲和力。以这种方式，它们的形成必定在细胞信号传导中发挥特定但仍未明确的作用，因此理解泛素密码信息至关重要。在这里，我们除了讨论对其生物学的当前理解之外，还讨论了杂合泛素/UbL链存在的证据。另一种UbL对泛素的修饰使事件时空顺序的破译变得复杂，这就需要开发一个杂合链工具箱。我们讨论了这一未满足的需求，并详细阐述了如何从我们先前建立的泛素蛋白酶体系统工具箱中创建定制工具，以专门靶向这些杂合泛素/UbL链。
