title: [Proteasome degradation of protein C and plasmin inhibitor mutants: molecular mechanism of congenital protein deficiency].
abstract: In many inherited disorders, protein deficiency is one of the major aetiologies, but the molecular and cellular mechanisms remain unclear. We investigated the intracellular degradation of mutant proteins, using naturally occurring PC and PI mutants that lead to congenital deficiencies. We have shown that proteasomes are very important for the degradation of PC and PI mutants, irrespective of the presence or absence of N-glycosylation moieties. Furthermore, mannose trimming after glucose removal is very important for initiation of the degradation. Inhibition of glucose trimming of the mutant proteins accelerated degradation by the proteasomes, and initiation of the degradation occurs after mannose trimming of the middle chain of N-linked glycosylation by mannosidase I. The binding of molecular chaperons influenced by the presence of N-glycosylation moieties may affect the efficient degradation of the mutant proteins. Cotransfection of endoplasmic reticulum (ER) degradation enhancing alpha-mannosidase like protein (EDEM) accelerated the degradation of N-glycosylated PC. The mutant PC or PI molecules were ubiquitin-independently degraded by proteasomes. Autophagy does not appear to contribute to the degradation of PC and PI mutants. These findings might help to elucidate the molecular mechanisms and potential treatments of congenital deficiencies of proteins in a system of coagulation and fibrinolysis.
authors.affiliation: Laboratory Molecular Genetics of Hematology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Miwako
authors.initials: M
authors.lastname: Nishio
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Koyama
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Hirosawa
mesh_terms: D000933:Antifibrinolytic Agents / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008358:Mannose / Q000378:metabolism; D008361:Mannosidases / Q000502:physiology; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D011486:Protein C / Q000235:genetics* / Q000378:metabolism*; D011488:Protein Deficiency / Q000151:congenital* / Q000235:genetics*
chemical_list: D000933:Antifibrinolytic Agents; D018832:Molecular Chaperones; D011486:Protein C; D008361:Mannosidases; C046090:mannosyl-oligosaccharide 1,2-alpha-mannosidase; D046988:Proteasome Endopeptidase Complex; D005947:Glucose; D008358:Mannose