Protein SUMOylation is a major post-translational modification essential for maintaining cellular homeostasis. SUMOylation has long been associated with stress responses as a diverse array of cellular stress signals are known to trigger rapid alternations in global protein SUMOylation. In addition, while there are large families of ubiquitination enzymes, all small ubiquitin-like modifiers (SUMOs) are conjugated by a set of enzymatic machinery comprising one heterodimeric SUMO-activating enzyme, a single SUMO-conjugating enzyme, and a small number of SUMO protein ligases and SUMO-specific proteases. How a few SUMOylation enzymes specifically modify thousands of functional targets in response to diverse cellular stresses remains an enigma. Here we review recent progress toward understanding the mechanisms of SUMO regulation, particularly the potential roles of liquid-liquid phase separation/biomolecular condensates in regulating cellular SUMOylation during cellular stresses. In addition, we discuss the role of protein SUMOylation in pathogenesis and the development of novel therapeutics targeting SUMOylation.

蛋白质 SUMO 化是维持细胞稳态所必需的主要翻译后修饰。SUMO 化长期以来一直与应激反应相关，因为已知多种细胞应激信号会触发整体蛋白质 SUMO 化的快速变化。此外，虽然存在大量泛素化酶家族，但所有小型泛素样修饰剂 (SUMO) 均由一组酶促机械进行缀合，其中包括一个异二聚体 SUMO 激活酶、单个 SUMO 缀合酶和少量 SUMO蛋白质连接酶和 SUMO 特异性蛋白酶。少数 SUMO 化酶如何特异性修饰数千个功能靶点以应对不同的细胞应激仍然是一个谜。在这里，我们回顾了了解 SUMO 调控机制的最新进展，特别是液-液相分离/生物分子缩合物在细胞应激过程中调节细胞 SUMO 化的潜在作用。此外，我们还讨论了蛋白质 SUMO 化在发病机制中的作用以及针对 SUMO 化的新型疗法的开发。