Cell Biology

Degraded but not Dishevelled

Science Signaling  10 Aug 2010:
Vol. 3, Issue 134, pp. ec244
DOI: 10.1126/scisignal.3134ec244

In the canonical Wnt pathway, Wnt signaling acts through the scaffold protein Dishevelled (Dvl) to stabilize β-catenin, enabling this transcription factor to induce expression of Wnt target genes. Gao et al. investigated whether the stability of Dvl was influenced by autophagy, a process in which ubiquitinated or aggregated proteins are degraded by the lysosome. β-catenin transcriptional activity in response to Wnt3a was decreased in cells treated with the mTOR inhibitor rapamycin or undergoing nutrient deprivation (both of which activate autophagy). In contrast, Wnt3a-induced β-catenin transcriptional activity was increased in Atg5–/– cells, which are deficient in a key regulatory protein in the autophagic pathway, or by knockdown of beclin 1, another autophagic regulatory protein, or of LC3, an autophagosome marker. Rapamycin and nutrient deprivation decreased the abundance of Dvl2, effects that were reversed by blocking autophagy or lysosomal function, and the turnover of Dvl2 during starvation was lower in Atg5–/– cells than in wild-type cells. In starved cells, Dvl2 localized to autophagosomes (as assessed by colocalization with GFP-tagged LC3) and showed increased interaction with LC3. Dvl2 self-aggregates through its DIX domain, and this domain was required for its interaction with LC3, ubiquitination of Dvl2, and degradation during starvation. The protein p62 directs ubiquitinated or aggregated proteins to the autophagosome through its interaction with LC3, and p62 promoted the interaction between Dvl2 and LC3, the localization of Dvl2 to autophagosomes, and the degradation of Dvl2 during starvation. Ubiquitination of Dvl2 required Von Hippel-Lindau protein (pVHL), a component of a ubiquitin E3 ligase complex. Knockdown of pVHL decreased the interaction between p62 and Dvl2, indicating that this interaction required the ubiquitination of Dvl2. In samples from individuals with late-stage colon cancer, the abundance of Dvl positively correlated with that of p62 and negatively correlated with that of Beclin 1. Thus, Wnt signaling is inhibited by autophagic degradation of Dvl, a process that may be dysregulated in colon cancer.

C. Gao, W. Cao, L. Bao, W. Zuo, G. Xie, T. Cai, W. Fu, J. Zhang, W. Wu, X. Zhang, Y.-G. Chen, Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation. Nat. Cell Biol. 12, 781–790 (2010). [PubMed]