Figure 1 Extrinsic and intrinsic pathways of apoptosis Figure 1 | Extrinsic and intrinsic pathways of apoptosis. In an example of the extrinsic pathway of apoptosis, the binding of Fas ligand (FasL) to its receptor Fas leads to the cleavage and activation of caspase 8. This proteolytic step is mediated by the adaptor protein Fas-associated death domain protein (FADD) and can be inhibited by FADD-like apoptosis regulator (also known as FLIP), a catalytically inactive homologue of caspase 8. Subsequently, caspase 8 cleaves and activates caspase 3 and caspase 7, which in turn induce the degradative phase of apoptosis. In the intrinsic pathway of apoptosis, the BCL-2 homology region 3 (BH3)-only proteins can either sequester anti-apoptotic proteins such as BCL-2, or directly activate the pro-apoptotic multi-BH3 proteins, such as BAK and BAX. Once the apoptotic signalling is initiated, BAK and BAX induce the release of cytochrome c from the mitochondrion. Subsequently, cytochrome c binds to APAF1 and forms a complex with pro-caspase 9 (apoptosome). Activation of caspase 9 in the apoptosome in turn induces apoptosis through the activation of caspase 3 and caspase 7. An alternative pathway of Fas-induced cell death involves crosstalk between the extrinsic and the intrinsic apoptotic pathways. This crosstalk is mediated by the truncated form of BID (tBID), which induces apoptosis by translocating to the mitochondrion. Cuda, C. M. et al. (2016) The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2016.132