我们对泛素编码的了解已经从传统的E1、E2和E3酶，通过单一类型的泛素链修饰特定底物的Lys残基大大发展到更复杂的过程，调节和介导泛泛素化。在本综述中，我们讨论了最近发现的内源性机制和病原体通过其前所未有的途径重写泛素编码以促进感染的过程。这些过程包括不规则的泛素修饰，涉及与蛋白质、脂质和糖的酯键连接，或通过涉及泛素Arg42的磷酸核糖桥的泛素化。我们还介绍了编写和反转这些修饰的酶途径，例如严重急性呼吸综合症冠状病毒（SARS-CoV）和SARS-CoV-2的凯特琳样蛋白酶。此外，结构研究揭示了泛素的最终功能不仅仅是通过泛素结合结构域简单识别的。相反，泛素化靶点或泛素链与其读取器（例如，蛋白酶体、MLL1复合物或DOT1L）之间的复杂的多价相互作用可以引发构象变化，以调节蛋白质降解或转录。新发现的机制为癌症和传染病等疾病提供了创新的治疗干预机会。©2022年Springer Nature Limited。

Our understanding of the ubiquitin code has greatly evolved from conventional E1, E2 and E3 enzymes that modify Lys residues on specific substrates with a single type of ubiquitin chain to more complex processes that regulate and mediate ubiquitylation. In this Review, we discuss recently discovered endogenous mechanisms and unprecedented pathways by which pathogens rewrite the ubiquitin code to promote infection. These processes include unconventional ubiquitin modifications involving ester linkages with proteins, lipids and sugars, or ubiquitylation through a phosphoribosyl bridge involving Arg42 of ubiquitin. We also introduce the enzymatic pathways that write and reverse these modifications, such as the papain-like proteases of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. Furthermore, structural studies have revealed that the ultimate functions of ubiquitin are mediated not simply by straightforward recognition by ubiquitin-binding domains. Instead, elaborate multivalent interactions between ubiquitylated targets or ubiquitin chains and their readers (for example, the proteasome, the MLL1 complex or DOT1L) can elicit conformational changes that regulate protein degradation or transcription. The newly discovered mechanisms provide opportunities for innovative therapeutic interventions for diseases such as cancer and infectious diseases.© 2022. Springer Nature Limited.