Alpha-synuclein negatively regulates Notchl intracellular domain protein stability through promoting interaction with Fbw7

摘要

Notch signaling pathway is well known that it is involved in regulating cell fate, proliferation and homeo-stasis. In this study, we show a novel function of alpha-synuclein (SNCA) to promote degradation of Notchl intracellular domain (Notchl-IC) through Fbw7, ubiquitin E3 ligase. We identified that SNCA inhibits Notchl transcription activity and diminishes the interaction between Notchl-IC and RBP-Jk. We also found decrease of Notchl-IC protein stability by exogenous and endogenous SNCA through protea-somal pathway, not through lysosomal pathway. And, we found that SNCA promotes interaction between Notchl-IC and Fbw7. Furthermore, SNCA directly interacts with Fbw7. SNCA increases ubiquitination of Notch-IC by Fbw7 through interaction with Fbw7. Together, these results suggest that SNCA is a novel regulator of Notchl-IC transcriptional activity with acting as an enhancer of the interaction of Notchl-IC and Fbw7 with increasing degradation of Notchl-IC.