Zou Ling, Liao Minru, Zhen Yongqi, Zhu Shiou, Chen Xiya, Zhang Jin, Hao Yue, Liu Bo
School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
Acta Pharm Sin B. 2022 Oct;12(10):3743-3782. doi: 10.1016/j.apsb.2022.06.004. Epub 2022 Jun 11.
UNC-51-like kinase 1 (ULK1), as a serine/threonine kinase, is an autophagic initiator in mammals and a homologous protein of autophagy related protein (Atg) 1 in yeast and of UNC-51 in ULK1 is well-known for autophagy activation, which is evolutionarily conserved in protein transport and indispensable to maintain cell homeostasis. As the direct target of energy and nutrition-sensing kinase, ULK1 may contribute to the distribution and utilization of cellular resources in response to metabolism and is closely associated with multiple pathophysiological processes. Moreover, ULK1 has been widely reported to play a crucial role in human diseases, including cancer, neurodegenerative diseases, cardiovascular disease, and infections, and subsequently targeted small-molecule inhibitors or activators are also demonstrated. Interestingly, the non-autophagy function of ULK1 has been emerging, indicating that non-autophagy-relevant ULK1 signaling network is also linked with diseases under some specific contexts. Therefore, in this review, we summarized the structure and functions of ULK1 as an autophagic initiator, with a focus on some new approaches, and further elucidated the key roles of ULK1 in autophagy and non-autophagy. Additionally, we also discussed the relationships between ULK1 and human diseases, as well as illustrated a rapid progress for better understanding of the discovery of more candidate small-molecule drugs targeting ULK1, which will provide a clue on novel ULK1-targeted therapeutics in the future.
UNC-51样激酶1（ULK1）作为一种丝氨酸/苏氨酸激酶，是哺乳动物中的自噬启动因子，是酵母中自噬相关蛋白（Atg）1以及秀丽隐杆线虫中UNC-51的同源蛋白。ULK1以激活自噬而闻名，自噬在蛋白质运输过程中具有进化保守性，对于维持细胞内稳态不可或缺。作为能量和营养感应激酶的直接靶点，ULK1可能参与细胞资源在代谢过程中的分配和利用，并与多种病理生理过程密切相关。此外，大量研究表明ULK1在包括癌症、神经退行性疾病、心血管疾病和感染在内的人类疾病中发挥关键作用，针对ULK1的小分子抑制剂或激活剂也已得到证实。有趣的是，ULK1的非自噬功能也逐渐被发现，这表明在某些特定情况下，与自噬无关的ULK1信号网络也与疾病相关。因此，在本综述中，我们总结了ULK1作为自噬启动因子的结构和功能，重点介绍了一些新进展，并进一步阐明了ULK1在自噬和非自噬中的关键作用。此外，我们还讨论了ULK1与人类疾病的关系，并展示了在更好地理解针对ULK1的更多候选小分子药物发现方面的快速进展，这将为未来新型ULK1靶向治疗提供线索。
