The life span of short-lived plasma cells is partly determined by a block on activation of apoptotic caspases acting in combination with endoplasmic reticulum stress.
Apoptosis of short-lived plasma cells after a few days of intense immunoglobulin secretion is critical for maintaining a controlled humoral immune response. The mechanisms that regulate this process are poorly understood. Here we report that the key apoptotic caspases, caspase-3 and caspase-9, become resistant to activation by apoptotic stimuli when B cells differentiate into short-lived plasma cells. As a consequence, apoptosis of most short-lived plasma cells in vitro and in vivo is effector caspase-independent. We also show that a triaspartic acid repeat that normally prevents activation of caspase-3 becomes stabilized in short-lived plasma cells and myeloma cell lines. The block on caspase activation occurs before the accumulation of intracellular immunoglobulins and a progressive rise in secretory stress in the endoplasmic reticulum (ER). Plasma cells show increased susceptibility to ER stress-induced apoptosis and activate the ER-associated caspase-12, which is required specifically for nuclear apoptotic events. In nonlymphoid cells that cannot activate effector caspases, programmed cell death is delayed in response to ER stress. These observations suggest that the block on activation of key apoptotic caspases has evolved in short-lived plasma cells to prolong survival under conditions of ER stress resulting from high-level immunoglobulin secretion.
Auner
Holger W
HW
Gene Regulation and Chromatin Group, Medical Research Council, Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, Du Cane Road, London, United Kingdom. holger.auner@csc.mrc.ac.uk
Beham-Schmid
Christine
C
Dillon
Niall
N
Sabbattini
Pierangela
P
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D053454:Caspase 12 / Q000276:immunology; D053148:Caspase 3 / Q000276:immunology*; D053453:Caspase 9 / Q000276:immunology*; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000276:immunology*; D006801:Humans; D008223:Lymphoma / Q000276:immunology; D051379:Mice; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology; D020449:Repetitive Sequences, Amino Acid
D053454:Caspase 12; D053148:Caspase 3; D053453:Caspase 9