B cell activation and differentiation employ mTORC1 rather than Xbp1 to initiate distinct segments of the unfolded protein response prior to antibody secretion

Abstract Little is known about how activated B cells build biosynthetic pathways and organelle structures needed for subsequent robust antibody secretion. The dominant model holds that newborn plasma cells adapt to increased antibody synthesis by activating the unfolded protein response (UPR) under the control of the transcription factor Xbp1. By analyzing gene expression with either activating or plasma cell-inductive signals we identified qualitatively distinct programs of UPR-affiliated genes preceding the onset of antibody secretion. Genetic loss of function experiments revealed that initial transcription of these loci required the mTORC1 kinase adaptor Raptor, but not Xbp1. Furthermore, single cell RNA-seq analysis of immature and long-lived plasma cells revealed that expression of activation-associated UPR genes correlated with apoptotic gene expression in a subset of plasma cells and in cycling plasma blasts. By contrast, UPR genes associated with true plasma cell induction were expressed broadly across steady state plasma cells including in cells experiencing high levels of pro-survival signaling. We conclude that B cells utilize mTORC1 to activate specialized UPR programs necessary to prepare for and optimize plasma cell function.