ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion Through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors

Abstract

SUMMARYThe extracellular aggregation of destabilized transthyretin (TTR) variants is implicated in the onset and pathogenesis of familial TTR-related amyloid diseases. One strategy to reduce toxic, extracellular aggregation of TTR is to decrease the population of aggregation-prone protein secreted from mammalian cells. Stress-independent activation of the unfolded protein response (UPR)-associated transcription factor ATF6 preferentially decreases secretion and subsequent aggregation of destabilized, aggregation-prone TTR variants. However, the mechanism of this reduced secretion was previously undefined. Here, we implement a mass spectrometry-based interactomics approach to identify endoplasmic reticulum (ER) proteostasis factors involved in ATF6-dependent reductions of destabilized TTR secretion. We show that ATF6 activation reduces amyloidogenic TTR secretion and subsequent aggregation through a mechanism involving ER retention that is mediated by increased interactions with ATF6-regulated ER proteostasis factors including BiP and PDIA4. Intriguingly, the PDIA4-dependent retention of TTR is independent of both the single TTR cysteine residue and the redox activity of PDIA4, indicating that PDIA4 retains destabilized TTR in the ER through a redox-independent chaperoning activity. Our results define a mechanistic basis to explain the ATF6 activation-dependent reduction of destabilized, amyloidogenic TTR secretion that could be therapeutically accessed to improve treatments of TTR-related amyloid diseases.

Hspa13 Regulates Endoplasmic Reticulum and Cytosolic Proteostasis Through Modulation of Protein Translocation

“…Consistent with this hypothesis, Hspa13 co-overexpression inhibits NKCC2 glycan maturation in HEK293 cells (36). To evaluate proteostasis of mature TTR, we exploited the well-characterized affinity of ER chaperones for destabilized TTR (78, 88, 89). Flag TTR was co-overexpressed with either Hspa13 or the other ER Hsp70, BiP.…”