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

John J Chen1, Joseph C Genereux1, Song Qu1

  • 1Department of Molecular and Experimental Medicine and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.

Chemistry & Biology
|December 3, 2014
PubMed

Insights

Activating the Unfolded Protein Response factor ATF6 enhances cellular protein quality control, reducing the secretion of disease-causing transthyretin variants and preventing toxic protein aggregation in systemic amyloid diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Biology

Background:

  • Systemic amyloidoses involve the aggregation of misfolded proteins into toxic structures.
  • Current therapies for extracellular protein aggregation are limited, highlighting the need for new strategies.

Purpose of the Study:

  • To investigate the role of ATF6 in regulating the secretion of amyloidogenic transthyretin (TTR) variants.
  • To explore ATF6 activation as a therapeutic strategy for systemic amyloid diseases.

Main Methods:

  • Inducing stress-independent activation of the transcription factor ATF6.
  • Assessing the impact of ATF6 activation on the secretion of TTR variants.
  • Evaluating the reduction in extracellular TTR aggregation.

Main Results:

  • ATF6 activation enhanced endoplasmic reticulum (ER) quality control stringency for TTR.
  • Secretion of destabilized, disease-associated TTR variants was preferentially reduced.
  • Extracellular aggregation of amyloidogenic TTRs into proteotoxic soluble aggregates was attenuated.

Conclusions:

  • Increasing ER quality control stringency via ATF6 activation is a viable strategy to reduce pathologic protein aggregation.
  • ATF6 activation offers a potential therapeutic approach for treating systemic amyloid diseases by targeting protein secretion and aggregation.

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