title: Endoplasmic Reticulum Proteostasis Influences the Oligomeric State of an Amyloidogenic Protein Secreted from Mammalian Cells.
abstract: 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.
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, 10550 North, Torrey Pines Road, MEM 220, La Jolla, CA 92037, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, 10550 North, Torrey Pines Road, MEM 220, La Jolla, CA 92037, USA; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Genereux
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Eul Hyun
authors.initials: EH
authors.lastname: Suh
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, 10550 North, Torrey Pines Road, MEM 220, La Jolla, CA 92037, USA.
authors.forename: Vincent F
authors.initials: VF
authors.lastname: Vartabedian
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, 10550 North, Torrey Pines Road, MEM 220, La Jolla, CA 92037, USA.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Rius
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, 10550 North, Torrey Pines Road, MEM 220, La Jolla, CA 92037, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Qu
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Maria T A
authors.initials: MTA
authors.lastname: Dendle
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, 10550 North, Torrey Pines Road, MEM 220, La Jolla, CA 92037, USA; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, 10550 North, Torrey Pines Road, MEM 220, La Jolla, CA 92037, USA; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: wiseman@scripps.edu.
authors.forename: R Luke
authors.initials: RL
authors.lastname: Wiseman
mesh_terms: D058227:Amyloidogenic Proteins / Q000032:analysis / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D057809:HEK293 Cells; D006801:Humans; D011228:Prealbumin / Q000032:analysis / Q000378:metabolism*; D066329:Protein Aggregates; D011487:Protein Conformation; D055503:Protein Multimerization; D055550:Protein Stability
chemical_list: D058227:Amyloidogenic Proteins; D011228:Prealbumin; D066329:Protein Aggregates
keywords: ER stress; Transthyretin; amyloid; extracellular proteostasis; misfolded protein secretion; protein aggregation; protein secretion