title: USP14 inhibits ER-associated degradation via interaction with IRE1alpha.
abstract: Accumulation of unfolded proteins within the endoplasmic reticulum (ER) lumen induces ER stress. Eukaryotic cells possess the ER quality control systems, the unfolded protein response (UPR), to adapt to ER stress. IRE1alpha is one of the ER stress receptors and mediates the UPR. Here, we identified ubiquitin specific protease (USP) 14 as a binding partner of IRE1alpha. USP14 interacted with the cytoplasmic region of IRE1alpha, and the endogenous interaction between USP14 and IRE1alpha was inhibited by ER stress. Overexpression of USP14 inhibited the ER-associated degradation (ERAD) pathway, and USP14 depletion by small interfering RNA effectively activated ERAD. These findings suggest that USP14 is a novel player in the UPR by serving as a physiological inhibitor of ERAD under the non-stressed condition.
authors.affiliation: Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Oral and Maxillofacial Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nagai
authors.forename: Hisae
authors.initials: H
authors.lastname: Kadowaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Maruyama
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Takeda
authors.forename: Hideki
authors.initials: H
authors.lastname: Nishitoh
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
mesh_terms: D004721:Endoplasmic Reticulum / Q000201:enzymology*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C509299:USP14 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D043222:Ubiquitin Thiolesterase