CHOP-independent apoptosis and pathway-selective induction of the UPR in developing plasma cells

Upon antigen stimulation, B lymphocytes differentiate into antibody secreting cells (ASC), most of which
undergo apoptosis after a few days of intense Ig production. Differentiation entails expansion of the
endoplasmic reticulum (ER) and requires XBP1 but not other elements of the unfolded protein response,
like PERK. Moreover, normal and malignant ASC are exquisitely sensitive to proteasome inhibitors, but the
underlying mechanisms are poorly understood. Here we analyze the role of C/EBP homologous protein
(CHOP), a transcription factor mediating apoptosis in many cell types that experience high levels of ER
stress. CHOP is transiently induced early upon B cell stimulation: covalent IgM aggregates form more
readily and IgM secretion is slower in chop−/− cells. Despite these subtle changes, ASC differentiation and
lifespan are normal in chop−/− mice. Unlike fibroblasts and other cell types, chop−/− ASC are equally or
slightly more sensitive to proteasome inhibitors and ER stressors, implying tissue-specific roles for CHOP
in differentiation and stress.