ATG4B inhibitor FMK-9a induces autophagy independent on its enzyme inhibition
ATG4B inhibitor FMK-9a induces autophagy independent on its enzyme inhibition
复制标题
ATG4B 抑制剂 FMK-9a 诱导自噬，不依赖于其酶抑制
DOI：
10.1016/j.abb.2018.03.001
复制
发表时间：
2018-04-15
影响因子：
3.9
通讯作者：
Li, Min
中科院分区：
文献类型：
--
作者：
Chu, Jiaqi;Fu, Yuanyuan;Li, Min
Atg 4是自噬体形成和Atg 8循环所必需的，具有加工前体和脂化Atg 8家族蛋白的功能。自噬活性异常与多种病理生理疾病有关，而ATG 4 B由于在自噬过程中的关键作用而成为潜在的治疗靶点。因此，非常需要ATG 4 B抑制剂。FMK-9a是迄今为止报道的最有效的抑制剂。在这项研究中，我们证实FMK-9a可以在体外和细胞中抑制ATG 4 B活性，IC 50为260 nM。此外，FMK-9a还能抑制pro-LC 3的裂解和LC 3-PE的脱脂。重要的是，FMK-9a可以诱导HeLa和MEF细胞中的自噬，而不管其对ATG 4 B活性的抑制。此外，FMK-9a诱导的自噬需要FIP 200和ATG 5。总之，我们证明了ATG 4 B抑制剂FMK-9a诱导自噬不依赖于其酶抑制。因此，FMK-9a可能在自噬过程中发挥多种作用，不能简单地将其视为ATG 4 B抑制剂。
Atg4 is essential for autophagosome formation and Atg8 recycle with the function of processing the precursor and the lipidated Atg8-family proteins. Abnormal autophagic activity is involved in a variety of pathophysiological diseases and ATG4B is of interest as a potential therapeutic target due to its key roles in autophagy process. So ATG4B inhibitors are highly needed. FMK-9a is the most potent inhibitor reported so far. In this study, we confirmed FMK-9a could suppress ATG4B activity in vitro and in cells, with an IC50 of 260 nM. Besides, FMK-9a could also attenuate the process of cleavage of pro-LC3 and the delipidation of LC3-PE. Importantly, FMK-9a could induce autophagy both in HeLa and MEF cells regardless of its inhibition on ATG4B activity. Moreover, FMK-9a induced autophagy required FIP200 and ATG5. In conclusion, we demonstrated that ATG4B inhibitor FMK-9a induces autophagy independent on its enzyme inhibition. Thus, FMK-9a may plays multiple roles in autophagy process and cannot simply take it as an ATG4B inhibitor.