Quantitative Interactome Proteomics Reveals a Molecular Basis for ATF6-Dependent Regulation of a Destabilized Amyloidogenic Protein

Abstract

Activation of the unfolded protein response (UPR)-associated transcription factor ATF6 has emerged as a promising strategy to selectively reduce the secretion and subsequent toxic aggregation of destabilized, amyloidogenic proteins implicated in diverse systemic amyloid diseases. However, the molecular mechanism by which ATF6 activation reduces the secretion of amyloidogenic proteins remains poorly defined. Here, we establish a quantitative interactomics platform with improved throughput and sensitivity to define how ATF6 activation selectively reduces secretion of a destabilized, amyloidogenic immunoglobulin light chain (LC) associated with Light Chain Amyloidosis (AL). We show that ATF6 activation increases the targeting of this destabilized LC to a select subset of pro-folding ER proteostasis factors that retains the amyloidogenic LC within the ER, preventing its secretion to downstream secretory environments. Our results define a molecular basis for the selective, ATF6-dependent reduction in destabilized LC secretion and highlight the advantage for targeting this endogenous UPR-associated transcription factor to reduce secretion of destabilized, amyloidogenic proteins implicated in AL and related systemic amyloid diseases.