Article
- The EMBO Journal (2006) 25, 1104 - 1113
- doi:10.1038/sj.emboj.7601009
Published online: 23 February 2006
Subject Categories:
Progressively impaired proteasomal capacity during terminal plasma cell differentiation
Simone Cenci1,2,a, Alexandre Mezghrani1,ab, Paolo Cascio3,a, Giada Bianchi1,2, Fulvia Cerruti3, Anna Fra4, Hugues Lelouard5, Silvia Masciarelli1,2, Laura Mattioli6, Laura Oliva1, Andrea Orsi1,2, Elena Pasqualetto1, Philippe Pierre5, Elena Ruffato1, Luigina Tagliavacca1 and Roberto Sitia1,2
- Department of Biology and Technology, DiBiT, San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
- Department of Veterinary Morphophysiology, University of Turin, Grugliasco (TO), Italy
- Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy
- Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM-Université de la Meditérannée, Marseille, France
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
Correspondence to:
Roberto Sitia, Department of Cell & Molecular Biology, Università Vita-Salute San Raffaele, DiBiT-HSR, Via Olgettina 58, Milan 20132, Italy. Tel.: +39 02 2643 4722; Fax: +39 02 2643 4723; E-mail: r.sitia@hsr.it
aThese authors contributed equally to this work
bPresent address: Institut Genetique Humaine, CNRS Montpellier, France
Received 13 October 2005; Accepted 26 January 2006
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, I
B
, and Bax), onset of apoptosis, and sensitization to proteasome inhibitors (PI). These events can be reproduced by expressing Ig-
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.
Keywords:
- apoptosis,
- myeloma,
- plasma cell,
- proteasome,
- unfolded protein response
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