ATF6 activation reduces the secretion and extracellular aggregation of destabilized variants of an amyloidogenic protein

John J. Chen, Joseph C. Genereux, Song Qu, John D. Hulleman, Matthew D. Shoulders, R. Luke Wiseman

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Systemic amyloidoses result from the aberrant secretion of destabilized, amyloidogenic proteins to the serum where they aggregate into proteotoxic soluble aggregates and amyloid fibrils. Few therapeutic approaches exist to attenuate extracellular pathologic aggregation of amyloidogenic proteins, necessitating the development of new strategies to intervene in these devastating disorders. We show that stress-independent activation of the Unfolded Protein Response-associated transcription factor ATF6 increases ER quality control stringency for the amyloidogenic protein transthyretin (TTR), preferentially reducing secretion of disease-associated TTR variants to an extent corresponding to the variants' destabilization of the TTR tetramer. This decrease in destabilized TTR variant secretion attenuates extracellular, concentration-dependent aggregation of amyloidogenic TTRs into soluble aggregates commonly associated with proteotoxicity in disease. Collectively, our results indicate that increasing ER quality control stringency through ATF6 activation is a strategy to attenuate pathologic aggregation of a destabilized, amyloidogenic protein, revealing a potential approach to intervene in systemic amyloid disease pathology.

Original languageEnglish (US)
Pages (from-to)1564-1574
Number of pages11
JournalChemistry and Biology
Volume21
Issue number11
DOIs
StatePublished - Nov 20 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Fingerprint

Dive into the research topics of 'ATF6 activation reduces the secretion and extracellular aggregation of destabilized variants of an amyloidogenic protein'. Together they form a unique fingerprint.

Cite this