PMID:21454619

Citation	Guo, X, Shen, S, Song, S, He, S, Cui, Y, Xing, G, Wang, J, Yin, Y, Fan, L, He, F and Zhang, L (2011) The E3 ligase Smurf1 regulates Wolfram syndrome protein stability at the endoplasmic reticulum. J. Biol. Chem. 286:18037-47
Abstract	The HECT-type ubiquitin ligase (E3) Smad ubiquitination regulatory factor 1 (Smurf1) targets various substrates, including Smad1/5, RhoA, Prickle 1, MEKK2, and JunB for degradation and thereby regulates adult bone formation and embryonic development. Here, we identify the endoplasmic reticulum (ER)-localized Wolfram syndrome protein (WFS1) as a specific degradation substrate of Smurf1. Mutations in the WFS1 gene cause Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy. WFS1 negatively regulates the ER stress response, and WFS1 deficiency in mice increases ER stress and triggers apoptosis. We show that Smurf1 interacts with WFS1 at the ER and promotes the ubiquitination and proteasomal degradation of WFS1. A C-terminal luminal region in WFS1, including residues 667-700, is involved in this degradation. Wild-type WFS1 as well as a subset of WFS1 mutants that include this degron region are susceptible to Smurf1-mediated degradation. By contrast, pathophysiological deletion mutants of WFS1 lacking the degron, such as W648X, Y660X, and Q667X, are resistant to degradation by Smurf1. Depletion of Smurf1 by RNA interference results in increased WFS1 and decreased ATF6α levels. Furthermore, we show that ER stress induces Smurf1 degradation and WFS1 up-regulation. These findings reveal for the first time that Smurf1 targets an ER-localized protein for degradation and that Smurf1 is regulated by ER stress.
Links	PubMed PMC3093877 Online version:10.1074/jbc.M111.225615
Keywords	Activating Transcription Factor 6/genetics; Activating Transcription Factor 6/metabolism; Amino Acid Substitution; Animals; Cell Line, Tumor; Endoplasmic Reticulum/genetics; Endoplasmic Reticulum/metabolism; HEK293 Cells; Humans; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Mutation, Missense; Protein Structure, Tertiary; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Unfolded Protein Response/physiology; Up-Regulation/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:SMUF1		GO:2000060: positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process	ECO:0000315:		P		Figure 4 shows how the mutation of this gene affects the regulation of the WFS1 protien	complete CACAO 7110
HUMAN:SMUF1	involved_in	GO:2000060: positive regulation of ubiquitin-dependent protein catabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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