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ATG4B inhibitor FMK-9a induces autophagy independent on its enzyme inhibition.

Archives of biochemistry and biophysics (2018-03-07)
Jiaqi Chu, Yuanyuan Fu, Jiecheng Xu, Xueping Zheng, Qianqian Gu, Xia Luo, Qi Dai, Shuxian Zhang, Peiqing Liu, Liang Hong, Min Li
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-α-Tubulin antibody, Mouse monoclonal, clone B-5-1-2, purified from hybridoma cell culture
Sigma-Aldrich
Earle′s Balanced Salts, With sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture