The Wnt signaling antagonist Dapper1 accelerates Dishevelled2 degradation via promoting its ubiquitination and aggregates-induced autophagy [Cell Biology]

March 30th, 2015 by Ma, B., Liu, B., Cao, W., Gao, C., Qi, Z., Ning, Y., Chen, Y.-G.

Autophagy is a regulated process that sequesters and transports cytoplasmic materials such as protein aggregates via autophagosomes to lysosomes for degradation. Dapper1 (Dpr1), an interacting protein of Dishevelled (Dvl), antagonizes Wnt signaling by promoting Dvl degradation via lysosomes. However, the mechanism is unclear. Here, we show that Dpr1 promotes the Von Hippel-Lindau tumor suppressor (VHL)-mediated ubiquitination of Dvl2 and its autophagic degradation. Knockdown of Dpr1 decreases the interaction between Dvl2 and pVHL, resulting in reduced ubiquitination of Dvl2. Dpr1-mediated autophagic degradation of Dvl2 depends on Dvl2 aggregation. Moreover, the aggregate-prone proteins Dvl2, p62 and the hungtingtin mutant Htt103Q promote autophagy in a Dpr1-dependent manner. These protein aggregates enhance the Beclin1-Vps34 interaction and Atg14L puncta formation, indicating that aggregated proteins stimulate autophagy initiation. Ubiquitination is not essential for the aggregates-induced autophagy initiation as inhibition of the ubiquitin-activation E1 enzyme activity did not block the aggregates-induced Atg14L puncta formation. Our findings suggest that Dpr1 promotes the ubiquitination of Dvl2 by pVHL and mediates the protein aggregates-elicited autophagy initiation.
  • Posted in Journal of Biological Chemistry, Publications
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