Implication of calpain in caspase activation during B cell clonal deletion

Abstract

In the absence of costimulating signals, B cell receptor (BCR) crosslinking on immature B cells triggers the apoptotic cell death program. In the WEHI-231 B cell lymphoma model, anti-IgM crosslinking triggers activation of caspase-7 independently of caspase-8, followed by apoptosis. Two main mechanisms for caspase-7 activation have been proposed: (i) caspase-8 recruitment to death receptors (Fas or tumour necrosis factor); and (ii) changes in mitochondrial membrane permeability and cytochrome c release, which activate caspase-9. Here we report that caspase-7 activation induced by BCR crosslinking is independent of caspase-8 and cytochrome c translocation from mitochondria to the cytosol, as well as of mitochondrial depolarization. In addition, in a cell-free system, the S-100 fraction of anti-IgM-treated WEHI-231 cells induces a caspase activation pattern different from that activated by cytochrome c and dATP. We demonstrate that calpain specifically triggers activation and processing of caspase-7 both in vitro and in vivo, and that both processes are inhibited by calpain inhibitors. Furthermore, calpain activation is associated with decreased expression levels of calpastatin, which is upregulated by CD40 ligation. These data confirm a role for calpain during BCR crosslinking, which may be critical for cell deletion by apoptosis during B cell development and activation.

Multiple death pathways in retina-derived 661W cells following growth factor deprivation: crosstalk between caspases and calpains

“…For instance, caspases facilitate calpain activity through the cleavage of its endogenous inhibitor calpastatin. 18,19 At the same time, calpains directly proteolyse executioner caspases, mediating their activation, 20,21 as well as proapoptotic Bcl-2 family members that eventually cause the release of apoptogenic factors from the mitochondria involved in the triggering of the caspase cascade. [22][23][24] While the time course of developmental apoptosis in the mouse retina has been extensively described in several studies, 10,[25][26][27] the biochemical death pathways involved are not fully understood.…”

Stage-specific expression of DNaseγ during B-cell development and its role in B-cell receptor-mediated apoptosis in WEHI-231 cells

“…8 Caspase-7 is thought to be the most important caspase in BCR-mediated apoptosis (Figure 8a). 25,26 BCR ligation induces the selective activation of caspase-7 via two independent cascades: a mitchondria caspase-9 pathway and a calpain pathway. 26,27 Calpain, which is a Ca 2 þ -dependent cysteine protease, is activated upon BCR ligation and catalyzes the processing of procaspase-7 into its active form.…”

“…25,26 BCR ligation induces the selective activation of caspase-7 via two independent cascades: a mitchondria caspase-9 pathway and a calpain pathway. 26,27 Calpain, which is a Ca 2 þ -dependent cysteine protease, is activated upon BCR ligation and catalyzes the processing of procaspase-7 into its active form. 26 BCR ligation also triggers a sustained Ca 2 þ influx in WEHI-231 cells, which is thought to be an important trigger of calpain activation.…”

“…26,27 Calpain, which is a Ca 2 þ -dependent cysteine protease, is activated upon BCR ligation and catalyzes the processing of procaspase-7 into its active form. 26 BCR ligation also triggers a sustained Ca 2 þ influx in WEHI-231 cells, which is thought to be an important trigger of calpain activation. 28 Concomitant signaling through CD40 is known to rescue WEHI-231 cells from BCR-mediated apoptosis.…”

“…29 Importantly, CD40 ligation induces the expression of the Bcl-2-like antiapoptotic protein A1 and the endogenous calpain inhibitor calpastatin. 26,30 A1 and calpastatin inhibit caspase-9 activation and calpain activity, respectively, thereby interfering with the activation of caspase-7.…”