Endoplasmic reticulum quality control regulates the fate of transthyretin variants in the cell

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 inv...

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Bibliographic Details
Published in:The EMBO journal 2007-05, Vol.26 (10), p.2501-2512
Main Authors: Sato, Takashi, Susuki, Seiko, Suico, Mary Ann, Miyata, Masanori, Ando, Yukio, Mizuguchi, Mineyuki, Takeuchi, Makoto, Dobashi, Mizuki, Shuto, Tsuyoshi, Kai, Hirofumi
Format: Article
Language:English
Subjects:
Aggregates
Amyloid - metabolism
amyloidosis
Amyloidosis - etiology
Amyloidosis - pathology
Animals
Carcinoma, Hepatocellular - pathology
Cell Line
Cell Line, Tumor
Cells
CHO Cells
Control systems
Cricetinae
Cricetulus
Disease
EMBO24
EMBO31
Endoplasmic Reticulum - metabolism
ER quality control
familial amyloid polyneuropathy (FAP)
Genetic Variation
Heat-Shock Proteins - genetics
Heat-Shock Proteins - metabolism
HSP90 Heat-Shock Proteins - genetics
HSP90 Heat-Shock Proteins - metabolism
Humans
Liver Neoplasms - pathology
Molecular biology
Molecular Chaperones - genetics
Molecular Chaperones - metabolism
Mutation
Prealbumin - chemistry
Prealbumin - genetics
Prealbumin - metabolism
Protein Folding
Proteins
Quality control
Retention
transthyretin
TTR variants
Up-Regulation
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Description
Summary: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.
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7601685