Endoplasmic Reticulum Proteostasis Influences the Oligomeric State of an Amyloidogenic Protein Secreted from Mammalian Cells. Issue 10 (20th October 2016)

• Record Type: Journal Article
• Authors: Chen, John J.; Genereux, Joseph C.; Suh, Eul Hyun; Vartabedian, Vincent F.; Rius, Bibiana; Qu, Song; Dendle, Maria T.A.; Kelly, Jeffery W.; Wiseman, R. Luke
• Is Part Of: Cell chemical biology. Volume 23:Issue 10(2016)
• Page Start: 1282
• Page End: 1293
• Publication Date: 2016-10-20
• Subjects: Transthyretin -- protein secretion -- ER stress -- extracellular proteostasis -- amyloid -- misfolded protein secretion -- protein aggregation; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.09.001
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Transthyretin (TTR) is a tetrameric serum protein associated with multiple systemic amyloid diseases. In these disorders, TTR aggregates in extracellular environments through a mechanism involving rate-limiting dissociation of the tetramer to monomers, which then misfold and aggregate into soluble oligomers and amyloid fibrils that induce toxicity in distal tissues. Using an assay established herein, we show that highly destabilized, aggregation-prone TTR variants are secreted as both native tetramers and non-native conformations that accumulate as high-molecular-weight oligomers. Pharmacologic chaperones that promote endoplasmic reticulum (ER) proteostasis of destabilized TTR variants increase their fraction secreted as a tetramer and reduce extracellular aggregate populations. In contrast, disrupting ER proteostasis reduces the fraction of destabilized TTR secreted as a tetramer and increases extracellular aggregates. These results identify ER proteostasis as a factor that can affect conformational integrity and thus toxic aggregation of secreted amyloidogenic proteins associated with the pathology of protein aggregation diseases. Highlights: Developed assay to measure transthyretin tetramers secreted from mammalian cells Highly destabilized TTR tetramers are secreted in non-native conformations Pharmacologic chaperoning promotes secretion of destabilized TTR tetramers Thapsigargin-induced ER stress reduces the quality of secreted TTR Abstract : Using a new assay to measure the oligomeric state of secreted transthyretin, Chen et al. show that chemical or biologic alterations in endoplasmic reticulum protein homeostasis can influence the extracellular aggregation of destabilized transthyretin variants associated with human amyloid diseases.