title: A dual role for EDEM1 in the processing of rod opsin.
abstract: Mutations in rod opsin, the archetypal G-protein-coupled receptor, cause retinitis pigmentosa. The majority of mutations, e.g. P23H, cause protein misfolding, resulting in ER retention, induction of the unfolded protein response and degradation by ERAD. If misfolded rod opsin escapes degradation, it aggregates and forms intracellular inclusions. Therefore, it is important to identify the chaperones that mediate the folding or degradation of rod opsin. ER degradation enhancing alpha-mannosidase-like 1 (EDEM1) can enhance the release of terminally misfolded glycoproteins from the calnexin chaperone system. Here, we identify EDEM1 as a novel chaperone of rod opsin. EDEM1 expression promoted the degradation of P23H rod opsin and decreased its aggregation. By contrast, shRNA-mediated knockdown of EDEM1 increased both the amount of P23H rod opsin and its aggregation into inclusions. EDEM1 was detected in rod photoreceptor inner segments and EndoH-sensitive rod opsin co-immunoprecipitated with EDEM1 from retina, suggesting that rod opsin is a physiological EDEM1 client. Unexpectedly, EDEM1 binding to rod opsin was independent of mannose trimming and EDEM1 promoted the cell-surface expression of mutant rod opsin. Collectively, the data suggest that EDEM1 is a chaperone for rod opsin and that expression of EDEM1 can be used to promote correct folding, as well as enhanced degradation, of mutant proteins in the ER to combat protein-misfolding disease.
authors.affiliation: UCL Institute of Ophthalmology, London, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Kosmaoglou
authors.forename: Naheed
authors.initials: N
authors.lastname: Kanuga
authors.forename: Mònica
authors.initials: M
authors.lastname: Aguilà
authors.forename: Pere
authors.initials: P
authors.lastname: Garriga
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
mesh_terms: D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D012160:Retina / Q000378:metabolism; D012243:Rhodopsin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C486654:EDEM1 protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones; D012243:Rhodopsin