Figure 9.

Illustration of LUBAC-mediated suppression of IL-21-induced apoptosis in CD154-stimulated B cells. (A) CD40 activation in B cells upregulates LUBAC-catalyzed linear M1-Ub, including that of cFLIP, which leads to cFLIP stabilization and inhibition of caspase 8 activation. LUBAC plays a minor role to the major role of RAB7 in CD40-triggered NF-κB activation in B cells. (B) CD40 activation also induces the expression of anti-apoptotic factor BCL2 and BCL-XL. IL-21, however, dampens such induction and also upregulates expression of pro-apoptotic factor BIM. The combined effects of BCL2/BCL-XL downregulation and BIM upregulation would activate pro-apoptotic BAX/BAK complex to increase the mitochondria permeability and cytochrome C release into the cytoplasm to activate caspase 9. (C) In the absence of LUBAC, caspase 8 activation would amplify a putative caspase network, within which multiple caspases, including caspase 9 and caspase 3, would be activated in a synchronized manner due to positive-feedback loops, leading to the irreversible apoptosis process.