Pivotal Advance: Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors

Journal of Leukocyte Biology

Giada Bianchi–²  Alexandre Mezghrani⁵  Mary Raule⁴  Fulvia Cerruti⁴  Enrico Milan³  Elena Pasqualetto¹  Roberto Sitia,  and³  Simone Cenci, ³  Paolo Cascio⁴  Laura Oliva¹ 

[1] Division of Genetics and Cell Biology, DiBiT, and Myeloma Unit, San Raffaele Scientific Institute, Milano, Italy;–Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA;Division of Genetics and Cell Biology, DiBiT, and Myeloma Unit, San Raffaele Scientific Institute, Milano, Italy;  Università Vita-Salute San Raffaele, Milano, Italy;Department of Veterinary Morphophysiology, University of Torino, Torino, Italy Myeloma Unit, San Raffaele Scientific Institute, Milano, Italy;Institut de Génomique Fonctionnelle, CNRS UMR503, INSERM U66, Montpellier, France;

关键词: immunoglobulin;    plasma cells;    proteostasis;    proteostenosis;   

DOI  :  10.1189/jlb.1011497

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

A previously unsuspected, considerable proportion of newly synthesized polypeptides are hydrolyzed rapidly by proteasomes, possibly competing with endogenous substrates and altering proteostasis. In view of the anti-cancer effects of PIs, we set out to achieve a quantitative assessment of proteasome workload in cells hallmarked by different PI sensitivity, namely, a panel of MM cells, and in a dynamic model of plasma cell differentiation, a process that confers exquisite PI sensitivity. Our results suggest that protein synthesis is a key determinant of proteasomal proteolytic burden and PI sensitivity. In different MM cells and in differentiating plasma cells, the average proteolytic work accomplished per proteasome ranges over different orders of magnitude, an unexpected degree of variability, with increased workload invariably associated to increased PI sensitivity. The unfavorable load-versus-capacity balance found in highly PI-sensitive MM lines is accounted for by a decreased total number of immunoproteasomes/cell coupled to enhanced generation of RDPs. Moreover, indicative of cause-effect relationships, attenuating general protein synthesis by the otherwise toxic agent CHX reduces PI sensitivity in activated B and in MM cells. Our data support the view that in plasma cells protein synthesis contributes to determine PI sensitivity by saturating the proteasomal degradative capacity. Quantitating protein synthesis and proteasome workload may thus prove crucial to design novel negative proteostasis regulators against cancer.

【 授权许可】

Unknown