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GEO help: Mouse over screen elements for information. |
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Status |
Public on Nov 04, 2015 |
Title |
IRE1alpha is an endogenous substrate of endoplasmic reticulum-associated degradation |
Organism |
Mus musculus |
Experiment type |
Expression profiling by array
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Summary |
Endoplasmic reticulum-associated degradation (ERAD) represents a principle quality control (QC) mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unknown. Here we discover that IRE1alpha, the sensor of unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. Mechanistically, ERAD-mediated IRE1alpha degradation occurs in a Bip-dependent manner under basal conditions and is attenuated in response to ER stress. Both intramembrane hydrophilic residues of IRE1alpha and lectin protein OS9 are required for IRE1alpha degradation. ERAD deficiency causes IRE1alpha protein stabilization, accumulation and mild activation both in vitro and in vivo, leading to cellular hypersensitivity to ER stress and inflammation. Furthermore, though enterocyte-specific Sel1L-knockout mice (Sel1LΔIEC) are viable and appear normal, they are more susceptible to experimental colitis in an IRE1alpha-dependent but CHOP-independent manner. Collectively, these results demonstrate that Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1alpha signaling in vivo by managing its protein turnover.
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Overall design |
Colon epithelium of wild type and enterocyte-specific Sel1L knockout mice were subjected to gene expression analysis.
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Contributor(s) |
Sun S, Shi G, Sha H, Ji Y, Han X, Shu X, Ma H, Takamasa I, Gao B, Bu P, Guber RD, Shen X, Lee AH, Iwawaki T, Paton AW, Paton JC, Fang D, Tsai B, Yates III JR, Wu H, Kersten S, Long Q, Duhamel GE, Simpson KW, Qi L |
Citation(s) |
26551274 |
Submission date |
Jul 06, 2015 |
Last update date |
Mar 04, 2019 |
Contact name |
Guido Hooiveld |
E-mail(s) |
guido.hooiveld@wur.nl
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Organization name |
Wageningen University
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Department |
Div. Human Nutrition & Health
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Lab |
Nutrition, Metabolism & Genomics Group
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Street address |
HELIX, Stippeneng 4
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City |
Wageningen |
ZIP/Postal code |
NL-6708WE |
Country |
Netherlands |
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Platforms (1) |
GPL6246 |
[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version] |
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Samples (6)
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GSM1810421 |
Colonic epithelium, wild type, replicate 1 |
GSM1810422 |
Colonic epithelium, wild type, replicate 2 |
GSM1810423 |
Colonic epithelium, wild type, replicate 3 |
GSM1810424 |
Colonic epithelium, Sel1L knockout, replicate 1 |
GSM1810425 |
Colonic epithelium, Sel1L knockout, replicate 2 |
GSM1810426 |
Colonic epithelium, Sel1L knockout, replicate 3 |
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Relations |
BioProject |
PRJNA289019 |
Supplementary file |
Size |
Download |
File type/resource |
GSE70563_RAW.tar |
24.4 Mb |
(http)(custom) |
TAR (of CEL) |
Processed data included within Sample table |
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