The special unfolded protein response in plasma cells*

The high rate of antibody production places considerable metabolic and folding stress on plasma cells (PC). Not surprisingly, they rely on the unfolded protein response (UPR), a universal signaling, and transcriptional network that monitors the health of the secretory pathway and mounts cellular responses to stress. Typically, the UPR utilizes three distinct stress sensors in the ER membrane, each regulating a subset of targets to re-establish homeostasis. PC use a specialized UPR scheme-they preemptively trigger the UPR via developmental signals and suppress two of the sensors, PERK and ATF6, relying on IRE1 alone. The specialized PC UPR program is tuned to the specific needs at every stage of development-from early biogenesis of secretory apparatus, to massive immunoglobulin expression later. Furthermore, the UPR in PC integrates with other pathways essential in a highly secretory cell-mTOR pathway that ensures efficient synthesis, autophagosomes that recycle components of the synthetic machinery, and apoptotic signaling that controls cell fate in the face of excessive folding stress. This specialized PC program is not shared with other secretory cells, for reasons yet to be defined. In this review, we give a perspective into how and why PC need such a unique UPR program.