Endoplasmic Reticulum Proteostasis Influences the Oligomeric State of an Amyloidogenic Protein Secreted from Mammalian Cells

John J. Chen, Joseph C. Genereux, Eul Hyun Suh, Vincent F. Vartabedian, Bibiana Rius, Song Qu, Maria T.A. Dendle, Jeffery W. Kelly, R. Luke Wiseman

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish
Pages (from-to)1282-1293
Number of pages12
JournalCell Chemical Biology
Volume23
Issue number10
DOIs
StatePublished - 20 Oct 2016

Keywords

  • ER stress
  • Transthyretin
  • amyloid
  • extracellular proteostasis
  • misfolded protein secretion
  • protein aggregation
  • protein secretion

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