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.
Department of Biology and Technology, DiBiT, San Raffaele Scientific Institute, Milan, Italy.
Simone
S
Cenci
Alexandre
A
Mezghrani
Paolo
P
Cascio
Giada
G
Bianchi
Fulvia
F
Cerruti
Anna
A
Fra
Hugues
H
Lelouard
Silvia
S
Masciarelli
Laura
L
Mattioli
Laura
L
Oliva
Andrea
A
Orsi
Elena
E
Pasqualetto
Philippe
P
Pierre
Elena
E
Ruffato
Luigina
L
Tagliavacca
Roberto
R
Sitia
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