In case of stress, hold tight: phosphorylation switches PDI from an oxidoreductase to a holdase, tuning ER proteostasis.

Eukaryotic cells have evolved multiple responses that allow endoplasmic reticulum (ER) homeostasis to be maintained even in the face of acute or chronic stresses. In this issue, Yu et al (2020) describe how site-specific phosphorylation switches protein disulfide isomerase (PDI) from a folding enzyme to a holdase chaperone which regulates ER stress responses, thus highlighting PDI as a key player in ER homeostasis.