Progressively impaired proteasomal capacity during terminal plasma cell differentiation

After few days of intense immunoglobulin (Ig) secretion,
most plasma cells undergo apoptosis, thus ending the
humoral immune response. We asked whether intrinsic
factors link plasma cell lifespan to Ig secretion. Here we
show that in the late phases of plasmacytic differentiation,
when antibody production becomes maximal, proteasomal
activity decreases. The excessive load for the reduced
proteolytic capacity correlates with accumulation of polyubiquitinated
proteins, stabilization of endogenous proteasomal
substrates (including Xbp1s, IkBalpha, and Bax),
onset of apoptosis, and sensitization to proteasome inhibitors
(PI). These events can be reproduced by expressing
Ig-mu chain in nonlymphoid cells. Our results suggest that a
developmental program links plasma cell death to protein
production, and help explaining the peculiar sensitivity of
normal and malignant plasma cells to PI.