The proteasome in terminal plasma cell differentiation.
The ability of eukaryotic cells to adapt to changing environmental conditions, respond to stimuli, and differentiate relies on their capacity to control the concentration, conformation, localization, and interaction of proteins, thereby reshaping their proteome. Protein degradation plays a critical role in maintaining protein homeostasis, and hence is carefully regulated. During the spectacular and demanding metamorphosis of activated B lymphocytes, expression programs are launched in coordinated waves, and adaptive strategies are deployed to prepare for antibody secretion. Surprisingly, though, despite increased demand for proteolysis, proteasome capacity collapses. As a result, antibody-secreting cells show symptoms of proteotoxic stress, and become extremely vulnerable to proteasome inhibition. The emerging concept that proteostenosis naturally follows B-cell activation has biological and immune implications, for it provides a model to dissect the integrated regulation of protein homeostasis, and a molecular counter limiting antibody responses, of use against autoimmune diseases. Mounting evidence linking proteotoxicity with proteasome vulnerability in malignant plasma cells visualizes strategies to understand responsiveness and obviate resistance to proteasome inhibition, with implications for the biology and therapy of plasma cell dyscrasias, namely, light chain amyloidosis and multiple myeloma.
Division of Genetics and Cell Biology, DiBiT, San Raffaele Scientific Institute, and Università Vita-Salute San Raffaele, Milano, Italy. cenci.simone@hsr.it
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D000686:Amyloidosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D010950:Plasma Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D007147:Immunoglobulin Light Chains; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex