Chu Yuanyuan, Dong Xingqi, Kang Yingjin, Liu Jingnan, Zhang Tao, Yang Cuiwei, Wang Zhangshun, Shen Wangchen, Huo Huanhuan, Zhuang Min, Lu Junxia, Liu Yanfen
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
iScience. 2020 Oct 21;23(11):101708. doi: 10.1016/j.isci.2020.101708. eCollection 2020 Nov 20.
AMFR/gp78 and USP13 are a pair of ubiquitin ligase and deubiquitinase that ensure the accuracy of endoplasmic reticulum-associated degradation (ERAD). Depletion of USP13 leads to caspase activation and cleavage of the ERAD chaperone BAG6, which is reversed by knockdown of . However, the mechanism and physiological relevance of this regulation are still unclear. Here, by using the NEDDylator system, we screened out TXN as a substrate of AMFR and USP13 and showed its involvement in regulating CASP3 activation and BAG6 cleavage. Furthermore, we showed that the cleaved N-terminal BAG6 is located in the cytosol and interacts with both LC3B-I and unprocessed form of LC3B (Pro-LC3B) through the LIR1 motif to suppress autophagy. An NMR approach verified the direct interaction between BAG6 LIR1 and LC3B-I or Pro-LC3B. Collectively, our findings uncover a mechanism that converts BAG6 from an ERAD regulator to an autophagy tuner and apoptosis inducer during ER stress.
AMFR/gp78和USP13是一对泛素连接酶和去泛素酶，可确保内质网相关降解（ERAD）的准确性。USP13的缺失会导致半胱天冬酶激活和ERAD伴侣蛋白BAG6的裂解，而这可通过敲低……来逆转。然而，这种调节的机制和生理相关性仍不清楚。在这里，我们使用NEDDylator系统筛选出TXN作为AMFR和USP13的底物，并表明其参与调节CASP3激活和BAG6裂解。此外，我们表明裂解后的BAG6 N端位于细胞质中，并通过LIR1基序与LC3B-I和未加工形式的LC3B（Pro-LC3B）相互作用以抑制自噬。一种核磁共振方法证实了BAG6 LIR1与LC3B-I或Pro-LC3B之间的直接相互作用。总的来说，我们的研究结果揭示了一种机制，即在内质网应激期间，BAG6从一个ERAD调节因子转变为自噬调节因子和凋亡诱导因子。
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