title: Endoplasmic reticulum quality control regulates the fate of transthyretin variants in the cell.
abstract: The secretion of transthyretin (TTR) variants contributes to the pathogenesis of amyloidosis because they form aggregates in the extracellular environment. However, the mechanism of how TTR variants pass the quality control system in the endoplasmic reticulum (ER) has not yet been elucidated. We investigated here the mechanism of how TTR passes ER monitoring. Monomeric mutation introduced in TTRs (M-TTRs) resulted in the ER retention of amyloidogenic M-TTRs but not non-amyloidogenic M-TTRs. Retention of amyloidogenic M-TTRs induced the unfolded protein response and upregulated the expression of ER chaperones BiP and glucose-regulated protein (GRP) 94. Additionally, we showed that the ER-retained amyloidogenic M-TTRs are subject to ER-associated degradation. On the other hand, the amyloidogenic TTR variants and non-amyloidogenic M-TTRs were secreted normally. These findings suggest that unlike for wild-type TTR, the ER quality control system may differentially regulate the fate of the TTR variants and their monomeric counterparts.
authors: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Takashi
authors: T
authors: Sato
authors: Seiko
authors: S
authors: Susuki
authors: Mary Ann
authors: MA
authors: Suico
authors: Masanori
authors: M
authors: Miyata
authors: Yukio
authors: Y
authors: Ando
authors: Mineyuki
authors: M
authors: Mizuguchi
authors: Makoto
authors: M
authors: Takeuchi
authors: Mizuki
authors: M
authors: Dobashi
authors: Tsuyoshi
authors: T
authors: Shuto
authors: Hirofumi
authors: H
authors: Kai
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000686:Amyloidosis / Q000209:etiology / Q000473:pathology; D000818:Animals; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D014644:Genetic Variation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017510:Protein Folding; D015854:Up-Regulation
chemical_list: D000682:Amyloid; D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011228:Prealbumin