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, IkappaBalpha, 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.
Cenci
Simone
S
Department of Biology and Technology, DiBiT, San Raffaele Scientific Institute, Milan, Italy.
Mezghrani
Alexandre
A
Cascio
Paolo
P
Bianchi
Giada
G
Cerruti
Fulvia
F
Fra
Anna
A
Lelouard
Hugues
H
Masciarelli
Silvia
S
Mattioli
Laura
L
Oliva
Laura
L
Orsi
Andrea
A
Pasqualetto
Elena
E
Pierre
Philippe
P
Ruffato
Elena
E
Tagliavacca
Luigina
L
Sitia
Roberto
R
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D007148:Immunoglobulin mu-Chains / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D009687:Nuclear Proteins / Q000378:metabolism; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D000071701:Regulatory Factor X Transcription Factors; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors; D025801:Ubiquitin / Q000378:metabolism*; D000071717:X-Box Binding Protein 1; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007075:Immunoglobulin M; D007148:Immunoglobulin mu-Chains; D008070:Lipopolysaccharides; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D009687:Nuclear Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D025801:Ubiquitin; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D051028:bcl-2-Associated X Protein; C485184:enhanced green fluorescent protein; D000072000:NF-KappaB Inhibitor alpha; D049452:Green Fluorescent Proteins