Cui D, Dai X, Shu J, Ma Y, Wei D, Xiong X, Zhao Y

?-transducin repeat-containing protein (?-TrCP), one of the best-characterized substrate recognition components of the SKP1-CUL1-F-box (SCF) E3 ligase, has two distinct paralogs, ?-TrCP1 and ?-TrCP2, expressed in mammals. Through governing the ubiquitination and degradation of numerous key regulators, ?-TrCP1/2 regulates various cellular physiological and pathological processes. However, whether and how these ...

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two proteins cross talk and whether they regulate cell autophagy and proliferation in different manners is completely unknown. Herein, we report that ?-TrCP1 and ?-TrCP2 are the physiological substrates of SCF E3 ligase and target each other for degradation that is dependent on their ?-TrCP degron sequences. Furthermore, glucose deprivation activates AMPK kinase to phosphorylate ?-TrCP1 and promotes the subsequent ubiquitination and degradation of ?-TrCP1 by ?-TrCP2, but does not promote ?-TrCP2 degradation by ?-TrCP1. Finally, we found that ?-TrCP2, not ?-TrCP1, preferentially degrades DEPTOR and REDD1, the inhibitors of mTORC1, to activate mTORC1, leading to autophagy inhibition and cell growth. Thus, our study demonstrates that ?-TrCP1 and ?-TrCP2 mutually target each other for degradation and that ?-TrCP2 acts as a dominant paralog in the regulation of cell autophagy and growth, which might be a promising anticancer target.

Date: Dec. 01, 2019

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