Progressively impaired proteasomal capacity during terminal plasma cell differentiation

Abstract

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, IjBa, and Bax), onset of apoptosis, and sensitization to proteasome inhibitors (PI). These events can be reproduced by expressing Ig-l 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.

Immunological memories of the bone marrow

“…It had been noted early on that they disappear from secondary lymphoid organs when immune reactions are finished,3, 4 an observation leading Astrid Fagraeus to state that the plasma cell is “a cell which has already passed its greatest functional activity” 3. A second observation apparently supported this view, in that plasma cells isolated from secondary lymphoid organs died rapidly in cell culture, unlike other lymphocytes 5, 6, 7, 8. The apparently short lifespan of plasma cells created a conceptual problem, namely how to explain the persistence of specific antibody titers in the blood, long after termination of an immune response 9.…”

Proteasome inhibitors: antitumor effects and beyond

“…18 Of particular interest is the recent observation that terminally differentiated immunoglobulin (Ig)-secreting plasma cells would have impaired proteasome activity. 19 The reduced proteolytic capacity is accompanied by accumulation of polyubiquitinated proteins, stabilization of substrates such as Ik-Ba and Bax, apoptosis induction and sensitization to proteasome inhibitors. This effect has been suggested to help control plasma cell lifespan and Ig production.…”

A RIDDle solved: Why an intact IRE1α/XBP‐1 signaling relay is key for humoral immune responses

“…Recently, Pengo et al have shown that autophagy indeed plays a role in dampening the antibody production, while paradoxically improving antibody yields [39]. In fact, autophagy protects "overzealous" antibodysecreting cells from a premature death caused by the proapoptotic effects of ER overload [39,40]. In support of a physiological need for curtailing μs through RIDD, a cursory BLAST search that we performed for this Commentary suggests that the μs "splice site" along with substantial stretches of flanking nucleotides is conserved in mammals.…”

“…B-cell activation has at least three direct consequences (top right): (i) Blimp1 is upregulated, orchestrating the reprogramming of the B cell to become a plasma cell; Blimp1 represses Pax5/BSAP, leading to increased XBP-1 expression [20]; (ii) initial ER expansion is triggered in anticipation of bulk antibody production [2,43] as part of the developmental program; (iii) at a later stage massive amounts of μs are produced which activate IRE1α-dependent XBP-1 splicing and XBP-1-s protein, further driving ER expansion. This feed-forward cycle ensures massive antibody production and limits plasma-cell life span [40]. RIDD may play a role in fine-tuning μs levels vis-à-vis the protein folding capacity in the ER, ultimately safeguarding full-gear antibody production [39].…”