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Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation

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Abstract

In eukaryotic cells, autophagy is a highly conserved self-digestion process to promote cell survival in response to nutrient starvation and other metabolic stresses. Autophagy is regulated by cell signalling such as the mTOR (mammalian target of rapamycin) pathway. However, the significance of autophagy in modulation of signal transduction is unclear. Here we show that autophagy negatively regulates Wnt signalling by promoting Dishevelled (Dvl) degradation. Von Hippel–Lindau protein-mediated ubiquitylation is critical for the binding of Dvl2 to p62, which in turn facilitates the aggregation and the LC3-mediated autophagosome recruitment of Dvl2 under starvation; the ubiquitylated Dvl2 aggregates are ultimately degraded through the autophagy–lysosome pathway. Moreover, a reverse correlation between Dvl expression and autophagy is observed in late stages of colon cancer development, indicating that autophagy may contribute to the aberrant activation of Wnt signalling in tumour formation.

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Figure 1: Autophagy attenuates Wnt signalling.
Figure 2: Autophagy induces Dvl degradation.
Figure 3: Starvation induces the autophagosome translocation of Dvl2 and promotes the interaction of Dvl2 with LC3.
Figure 4: Aggregation of Dvl2 is critical for its LC3 binding, ubiquitylation and concomitant autophagic degradation.
Figure 5: p62 promotes Dvl2–LC3 interaction and Dvl2 degradation under starvation conditions.
Figure 6: pVHL promotes Dvl2 ubiquitylation and degradation by means of autophagy.
Figure 7: Negative correlation between Dvl protein levels and autophagy in human colon cancer.

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  • 21 July 2010

    In the version of this article initially published online, Fig. 3f, Fig. 4a,b and Fig. 6g were incorrectly labelled. These errors has been corrected in both the HTML and PDF versions of the article.

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Acknowledgements

We thank Terje Johansen for p62 constructs, Long Yu for human LC3 construct, Noboru Mizushima for Atg5−/− MEFs, Masaaki Komatsu for Atg7−/− MEFs, and Li Yu, Roel Nusse, Daniel J. Klionsky, Juan Liang and Zhao Chen for suggestions. This work was supported by grants from the National Natural Science Foundation of China (30930050 and 30921004) and the 973 Program (2006CB943401 and 2010CB833706) to Y.-G.C.

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C.G.., W.C., L.B., J.Z., W.W., X.Z. and Y.-G.C. designed the experiments and analysed data. C.G., W.C., L.B., W.Z., G.X., T.C. and W.F. performed the experiments. C.G. and Y.-G.C. wrote the manuscript.

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Correspondence to Ye-Guang Chen.

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Gao, C., Cao, W., Bao, L. et al. Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation. Nat Cell Biol 12, 781–790 (2010). https://doi.org/10.1038/ncb2082

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