title: The Wnt Signaling Antagonist Dapper1 Accelerates Dishevelled2 Degradation via Promoting Its Ubiquitination and Aggregate-induced Autophagy.
abstract: 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 Dishevelled 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 huntingtin 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 aggregate-induced autophagy initiation as inhibition of the ubiquitin-activation E1 enzyme activity did not block the aggregate-induced Atg14L puncta formation. Our findings suggest that Dpr1 promotes the ubiquitination of Dvl2 by pVHL and mediates the protein aggregate-elicited autophagy initiation.
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Benyu
authors.initials: B
authors.lastname: Ma
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Bofeng
authors.initials: B
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Weipeng
authors.initials: W
authors.lastname: Cao
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Chan
authors.initials: C
authors.lastname: Gao
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Qi
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yuanheng
authors.initials: Y
authors.lastname: Ning
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China ygchen@tsinghua.edu.cn.
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D000072261:Dishevelled Proteins; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins; D051381:Rats; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491683:DACT1 protein, human; C000606581:DVL2 protein, human; C503247:Dact1 protein, rat; D000072261:Dishevelled Proteins; C000606582:Dvl2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D025801:Ubiquitin; C508545:frodo protein, mouse; D049452:Green Fluorescent Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; C494469:VHL protein, mouse
keywords: Dishevelled; Dpr1; autophagy; p62 (sequestosome 1(SQSTM1)); pVHL; protein aggregation; protein degradation; ubiquitylation (ubiquitination)
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