title: Prevention of aberrant protein aggregation by anchoring the molecular chaperone αB-crystallin to the endoplasmic reticulum.
abstract: The chaperone αB-crystallin (αBC) is a member of the small heat shock protein family and its point or truncated mutants cause the muscular disorder α-crystallinopathy. The illness is histologically characterized by accumulation of protein aggregates in muscle cells. Expression of the myopathy-causing R120G mutant of αBC, harboring an arginine-to-glycine mutation at position 120, results in aggregate formation. We demonstrated that tethering αBC to the endoplasmic reticulum (ER) membrane represses the protein aggregation mediated by the R120G mutant. ER-anchored αBC decreased the amount of the R120G mutant through autophagic proteolysis. In contrast, knockdown of ATG5, an E3 ligase essential for autophagy, in ER-anchored αBC-transfected cells restored the quantity of the R120G mutant. In this context, aggregate formation was still suppressed, indicating that ER-anchored αBC profoundly constrains aggregation competency of the R120G mutant separately from downregulating the abundance of the mutant. We have proposed that protein aggregation is prevented by manipulation of the ER microenvironment with αBC, and have shed light on a novel aspect of the ER as a therapeutic target.
authors.affiliation: Department of Molecular Cell Biology and Medicine, Institute of Health Biosciences, Tokushima University Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular Cell Biology and Medicine, Institute of Health Biosciences, Tokushima University Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Yamashita
authors.affiliation: Department of Molecular Cell Biology and Medicine, Institute of Health Biosciences, Tokushima University Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Naokatu
authors.initials: N
authors.lastname: Arakaki
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Health Biosciences, Tokushima University Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Nemoto
authors.affiliation: Department of Molecular Cell Biology and Medicine, Institute of Health Biosciences, Tokushima University Graduate School, 1-78-1, Sho-machi, Tokushima 770-8505, Japan. Electronic address: tyamazak@tokushima-u.ac.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yamazaki
mesh_terms: D001343:Autophagy; D003513:Cycloheximide / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D009135:Muscular Diseases / Q000473:pathology; D009154:Mutation; D066263:Protein Aggregation, Pathological / Q000517:prevention & control*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D038203:alpha-Crystallin B Chain; D049452:Green Fluorescent Proteins; D003513:Cycloheximide
keywords: Endoplasmic reticulum; Protein aggregation; R120G mutant; α-Crystallinopathy; αB-crystallin