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

Chen JJ, Genereux JC, Qu S, Hulleman JD, Shoulders MD, Wiseman RL
Chem Biol. 2014 21 (11): 1564-74

PMID: 25444553 · PMCID: PMC4254654 · DOI:10.1016/j.chembiol.2014.09.009

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.

Copyright © 2014 Elsevier Ltd. All rights reserved.

MeSH Terms (13)

ADP-Ribosylation Factors Amino Acid Substitution Endoplasmic Reticulum HEK293 Cells Hep G2 Cells Humans Kinetics Prealbumin Protein Stability Recombinant Fusion Proteins Tetrahydrofolate Dehydrogenase Transfection Unfolded Protein Response

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