The ubiquitin system has become synonymous with the modification of lysine residues. However, the substrate scope and diversity of the conjugation machinery have been underappreciated, bringing us to an epoch in ubiquitin system research. The striking discoveries of metazoan enzymes dedicated toward serine and threonine ubiquitination have revealed the important role of nonlysine ubiquitination in endoplasmic reticulum–associated degradation, immune signaling and neuronal processes, while reports of nonproteinaceous substrates have extended ubiquitination beyond the proteome. Bacterial effectors that bypass the canonical ubiquitination machinery and form unprecedented linkage chemistry further redefine long-standing dogma. While chemical biology approaches have advanced our understanding of the canonical ubiquitin system, further study of noncanonical ubiquitination has been hampered by a lack of suitable tools. This Perspective aims to consolidate and contextualize recent discoveries and to propose potential applications of chemical biology, which will be instrumental in unraveling this new frontier of ubiquitin research.

泛素系统已成为赖氨酸残基修饰的代名词。然而，共轭机制的底物范围和多样性一直被低估，这使我们进入了泛素系统研究的新纪元。专用于丝氨酸和苏氨酸泛素化的后生动物酶的惊人发现揭示了非赖氨酸泛素化在内质网相关降解、免疫信号和神经元过程中的重要作用，而非蛋白质底物的报道已将泛素化扩展到蛋白质组之外。绕过经典泛素化机制并形成前所未有的连锁化学的细菌效应子进一步重新定义了长期存在的教条。虽然化学生物学方法提高了我们对典型泛素系统的理解，由于缺乏合适的工具，对非规范泛素化的进一步研究受到阻碍。这一观点旨在巩固和结合最近的发现，并提出化学生物学的潜在应用，这将有助于揭示泛素研究的这一新前沿。