SIRT1 suppresses cellular accumulation of ß-TrCP E3 ligase via protein degradation.

ABSTRACT

ß-Transducin repeat-containing protein (ß-TrCP), an E3 ligase, promotes the degradation of substrate proteins in response to various stimuli. Even though several ß-TrCP substrates have been identified to date, limited information of its upstream regulators is available. Here, we showed that SIRT1 suppresses ß-TrCP protein synthesis via post-translational degradation. SIRT1 depletion led to a significant increase in the ß-TrCP accumulation without affecting the mRNA level. Consistently, ß-TrCP protein accumulation induced by resveratrol was further enhanced upon SIRT1 depletion. Rescue of SIRT1 reversed the effect of resveratrol, leading to reduced ß-TrCP protein levels. Proteasomal inhibition led to recovery of ß-TrCP in cells with SIRT1 overexpression. Notably, the recovered ß-TrCP colocalized mostly with SIRT1. Thus, SIRT1 acts as a negative regulator of ß-TrCP synthesis via promoting protein degradation.