Ca(2+)-driven PDIA6 biomolecular condensation ensures proinsulin folding.

The endoplasmic reticulum (ER) plays crucial roles in maintaining protein quality control and regulating dynamic Ca(2+) storage in eukaryotic cells. However, the proteostasis system involved in ER-mediated protein quality control has not been fully characterized. Here we show that Ca(2+) triggers the condensation of PDIA6, an ER-resident disulfide isomerase and molecular chaperone, into quality control granules. In contrast to the condensation mechanism observed for proteins containing low-complexity domains, our results indicate that transient but specific electrostatic interactions occur between the first and the third folded thioredoxin-like domains of PDIA6. We further show that the PDIA6 condensates recruit proinsulin, thereby accelerating the oxidative proinsulin folding and suppressing the proinsulin aggregation inside quality control granules, essential for secretion of insulin.