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PMID: 16498407 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Progressively impaired proteasomal capacity during terminal plasma cell differentiation.

The EMBO journal ·Vol. 25 ·No. 5 ·2006-03-08 ·Pages 1104-13

Cenci S, Mezghrani A, Cascio P, Bianchi G, Cerruti F, Fra A, Lelouard H, Masciarelli S, Mattioli L, Oliva L, Orsi A, Pasqualetto E, Pierre P, Ruffato E, Tagliavacca L, Sitia R

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, 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.

MeSH Terms
Animals Apoptosis Cell Differentiation DNA-Binding Proteins/metabolism Green Fluorescent Proteins/genetics,metabolism HeLa Cells/drug effects,metabolism Humans I-kappa B Proteins/metabolism Immunoglobulin M/metabolism Immunoglobulin mu-Chains/metabolism Lipopolysaccharides/pharmacology Mice Mice, Inbred C57BL Mice, Transgenic NF-KappaB Inhibitor alpha Nuclear Proteins/metabolism Plasma Cells/metabolism,pathology Protease Inhibitors/pharmacology Proteasome Inhibitors Regulatory Factor X Transcription Factors Spleen/cytology,drug effects,metabolism Transcription Factors Ubiquitin/metabolism X-Box Binding Protein 1 bcl-2-Associated X Protein/metabolism
Chemicals
DNA-Binding Proteins I-kappa B Proteins Immunoglobulin M Immunoglobulin mu-Chains Lipopolysaccharides NFKBIA protein, human Nfkbia protein, mouse Nuclear Proteins Protease Inhibitors Proteasome Inhibitors Regulatory Factor X Transcription Factors Transcription Factors Ubiquitin X-Box Binding Protein 1 XBP1 protein, human Xbp1 protein, mouse bcl-2-Associated X Protein enhanced green fluorescent protein NF-KappaB Inhibitor alpha Green Fluorescent Proteins
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Cenci Simone
Department of Biology and Technology, DiBiT, San Raffaele Scientific Institute, Milan, Italy.
Mezghrani Alexandre
Cascio Paolo
Bianchi Giada
Cerruti Fulvia
Fra Anna
Lelouard Hugues
Masciarelli Silvia
Mattioli Laura
Oliva Laura
Orsi Andrea
Pasqualetto Elena
Pierre Philippe
Ruffato Elena
Tagliavacca Luigina
Sitia Roberto
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7601009
Published
2006-03-08
Epub
2006-00-23
Pages
1104-13
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1409720
Subset
IM
Grants
Telethon · GP0117Y01 · Italy
External Links
PubMed source DOI: 10.1038/sj.emboj.7601009 PMC Full Text View journal details
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