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The Wnt Signaling Antagonist Dapper1 Accelerates Dishevelled2 Degradation via
Promoting Its Ubiquitination and Aggregate-induced Autophagy
#MMPMID25825496
Ma B
; Liu B
; Cao W
; Gao C
; Qi Z
; Ning Y
; Chen YG
J Biol Chem
2015[May]; 290
(19
): 12346-54
PMID25825496
show ga
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.
|*Gene Expression Regulation
[MESH]
|Adaptor Proteins, Signal Transducing/*metabolism
[MESH]
|Animals
[MESH]
|Autophagy
[MESH]
|Cell Line
[MESH]
|Dishevelled Proteins
[MESH]
|Green Fluorescent Proteins/metabolism
[MESH]
|HEK293 Cells
[MESH]
|Humans
[MESH]
|Intracellular Signaling Peptides and Proteins/*metabolism
[MESH]
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