| First Author | Sun S | Year | 2015 |
| Journal | Nat Cell Biol | Volume | 17 |
| Issue | 12 | Pages | 1546-55 |
| PubMed ID | 26551274 | Mgi Jnum | J:230750 |
| Mgi Id | MGI:5763707 | Doi | 10.1038/ncb3266 |
| Citation | Sun S, et al. (2015) IRE1alpha is an endogenous substrate of endoplasmic-reticulum-associated degradation. Nat Cell Biol 17(12):1546-55 |
| abstractText | Endoplasmic reticulum (ER)-associated degradation (ERAD) represents a principle quality control mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unexplored. Here we discover that IRE1alpha, the sensor of the unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. ERAD-mediated IRE1alpha degradation occurs under basal conditions in a BiP-dependent manner, requires both the intramembrane hydrophilic residues of IRE1alpha and the lectin protein OS9, and is attenuated by ER stress. ERAD deficiency causes IRE1alpha protein stabilization, accumulation and mild activation both in vitro and in vivo. Although enterocyte-specific Sel1L-knockout mice (Sel1L(DeltaIEC)) are viable and seem normal, they are highly susceptible to experimental colitis and inflammation-associated dysbiosis, in an IRE1alpha-dependent but CHOP-independent manner. Hence, Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1alpha signalling in vivo by managing its protein turnover. |
