Antibody-secreting cells integrate efficient NMD with non‑canonical UPR signaling to maintain proteostasis and support massive immunoglobulin synthesis
Abstract
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.
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BibTeX
@article{praite2026antibodysecreting,
title = {{Antibody-secreting cells integrate efficient NMD with non‑canonical UPR signaling to maintain proteostasis and support massive immunoglobulin synthesis}},
author = {Antoine Praité and Jean-Marie Lambert and Mohamad Omar Ashi and E Troadec and Christelle Oblet and Bastien Carle and Faraj Terro and Nivine Srour and Ophélie Dézé and Michel Cogné and Soazig Le Pennec and Christophe Sirac and Brice Laffleur and Sandy Al Hayek and Laurent Delpy},
journal = {Journal of Molecular Biology},
year = {2026},
month = oct,
doi = {10.1016/j.jmb.2026.169919},
url = {https://hal.science/hal-05684132v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Antibody-secreting cells integrate efficient NMD with non‑canonical UPR signaling to maintain proteostasis and support massive immunoglobulin synthesis
AU - Antoine Praité
AU - Jean-Marie Lambert
AU - Mohamad Omar Ashi
AU - E Troadec
AU - Christelle Oblet
AU - Bastien Carle
AU - Faraj Terro
AU - Nivine Srour
AU - Ophélie Dézé
AU - Michel Cogné
AU - Soazig Le Pennec
AU - Christophe Sirac
AU - Brice Laffleur
AU - Sandy Al Hayek
AU - Laurent Delpy
PY - 2026
DA - 2026/10/15
JO - Journal of Molecular Biology
DO - 10.1016/j.jmb.2026.169919
UR - https://hal.science/hal-05684132v1
AB - 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.
SN - 0022-2836
SN - 1089-8638
ER -