title: The Endoplasmic Reticulum-associated Degradation of Transthyretin Variants Is Negatively Regulated by BiP in Mammalian Cells.
abstract: Amyloid fibril formation of mutant transthyretin (TTR) that causes familial amyloid polyneuropathy occurs in the extracellular space. Thus, secretion of TTR variants contributes to the pathogenesis of amyloidosis. However, the molecular mechanisms underlying the endoplasmic reticulum (ER) exit or retention and subsequent degradation of TTR variants remain unclear. Here, we demonstrated that the nonsecreted TTR variants, such as D18G TTR and amyloidogenic TTRs with introduced monomeric mutation (M-TTRs), stably interact with the ER chaperone BiP in mammalian cells. These proteins were co-secreted with the secreted form of BiP in which the KDEL signal was removed, indicating that BiP partially contributes to the ER retention of nonsecreted TTR variants. More interestingly, the degradation efficiency of nonsecreted TTRs was increased when BiP was down-regulated by small interfering RNA. Thus, BiP protects the TTR variants from immediate degradation. Additionally, we showed that the stability of nonsecreted TTR variants is not disturbed in the coat complex II-deficient conditions, which are enough to inhibit the ER export of secreted TTR variants, including wild-type TTR. Therefore, the post-ER retrieval mechanism might not contribute to the ER-associated degradation of nonsecreted TTR variants. These findings suggest that the affinity to the ER-resident protein BiP regulates the fate of TTR variants in the ER.
authors.affiliation: Department of Molecular Medicine, Faculty of Medical and Pharmaceutical Sciences, Global Centers of Excellence "Cell Fate Regulation Research and Education Unit," Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Susuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyata
authors.forename: Mamiko
authors.initials: M
authors.lastname: Momohara
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Suico
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D017772:Amyloid Neuropathies / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000235:genetics; D021381:Protein Transport / Q000235:genetics
chemical_list: D000682:Amyloid; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011228:Prealbumin; D021382:Protein Sorting Signals