The Chaperone BAG6 Regulates Cellular Homeostasis between Autophagy and Apoptosis by Holding LC3B

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 AMFR. 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.