Antibody-secreting Cells Integrate Efficient NMD With Non‑canonical UPR Signaling to Maintain Proteostasis and...

Plasma cells are terminally differentiated B lymphocytes specialized in the high‑level production and secretion of antibodies. To accommodate the persistent load imposed on the endoplasmic reticulum (ER), plasma cell differentiation engages a sustained unfolded protein response (UPR). Although the UPR is known to attenuate nonsense‑mediated mRNA decay (NMD) in many cell types, the interplay between these pathways during plasma cell differentiation remains poorly defined. We show that NMD is rapidly enhanced during B cell activation and remains high in antibody‑secreting cells (ASCs), even as these cells activate the UPR. Using mouse models enabling in vivo monitoring of NMD under enforced ER stress, we identify limited activation of the PERK-eIF2α axis as a key determinant preserving NMD activity while supporting robust immunoglobulin synthesis. Supporting a key role for NMD in B cell activation and ASC differentiation, antisense oligonucleotide‑mediated knockdown of Upf1 severely compromised cell viability. Moreover, we provide evidence for efficient degradation of endogenous NMD substrates in myeloma cells, suggesting a functional role for NMD in multiple myeloma. Taken together, these findings reveal an integrated protein quality‑control network in ASCs that relies on the coordinated action of NMD and non‑canonical UPR signaling to maintain proteostasis and support massive immunoglobulin synthesis.