Intramembrane client recognition potentiates the chaperone functions of calnexin.

One-third of the human proteome is comprised of membrane proteins, which are particularly vulnerable to misfolding and often require folding assistance by molecular chaperones. Calnexin (CNX), which engages client proteins via its sugar-binding lectin domain, is one of the most abundant ER chaperones, and plays an important role in membrane protein biogenesis. Based on mass spectrometric analyses, we here show that calnexin interacts with a large number of nonglycosylated membrane proteins, indicative of additional nonlectin binding modes.

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.