Proteostasis and “redoxtasis” in the secretory pathway: Tales of tails from ERp44 and immunoglobulins

• Professional secretory cells must couple efficiency and fidelity in their protein factories.
• This requires the coordinated activity of numerous homeostatic and signaling networks.
• ERp44 is a multifunctional chaperone that operates at the ER–Golgi interface.
• ERp44 contributes to the regulation of calcium flux, redox homeostasis, and protein quality control.
• This review summarizes some molecular tales stemming from the polypeptide tails of ERp44 at its clients.

In multicellular organisms, some cells are given the task of secreting huge quantities of proteins. To comply with their duty, they generally equip themselves with a highly developed endoplasmic reticulum (ER) and downstream organelles in the secretory pathway. These professional secretors face paramount proteostatic challenges in that they need to couple efficiency and fidelity in their secretory processes. On one hand, stringent quality control (QC) mechanisms operate from the ER onward to check the integrity of the secretome. On the other, the pressure to secrete can be overwhelming, as for instance on antibody-producing cells during infection. Maintaining homeostasis is particularly hard when the products to be released contain disulfide bonds, because oxidative folding entails production of reactive oxygen species. How are redox homeostasis (“redoxtasis”) and proteostasis maintained despite the massive fluxes of cargo proteins traversing the pathway? Here we describe recent findings on how ERp44, a multifunctional chaperone of the secretory pathway, can modulate these processes integrating protein QC, redoxtasis, and calcium signaling.

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