Molecular pathways of PCD. To date, at least three different PCD molecular pathways have been recognized: the mitochondrial pathway (also called intrinsic), the death receptor pathway (also called extrinsic), and the ER pathway. In the mitochondrial PCD pathway, translocation of the proapoptotic protein Bax and the BH3-domain-only protein Bid from the cytosol to the mitochondria promotes cell death by inducing the release of cytochrome c (Cyt. c)from the mitochondria to the cytosol; although both full-length and truncated Bid (t-Bid) translocate to the mitochondria, t-Bid is the most biologically active form. Once in the cytosol, cytochrome c activates caspase-9 in the presence of Apaf-1, which, in turn, activates downstream executioner caspases. This pathway can be inhibited by the antiapoptotic protein Bcl-2 and by the protein caspase inhibitor X chromosome–linked inhibitor of apoptosis (XIAP). In the death receptor pathway, caspase-8 is activated by death receptors (members of the TNFR family) in the plasma membrane via the intermediary of adapter proteins. Death receptors include Fas (CD95) and the low-affinity neurotrophin receptor (p75^NTR). Activated caspase-8 then activates executioner caspases, directly or indirectly, through the activation of Bid. Stress in the ER, including disruption of ER-calcium homeostasis and accumulation of excess proteins in the ER, can also result in apoptosis through activation of caspase-12. This caspase is not activated by membrane- or mitochondria-targeted apoptotic signals. Activation of the upstream caspase-1, the key enzyme responsible for the activation of IL-1, also results in activation of executioner caspases and enhances, at least in part through the cleavage of Bid, the activation of the mitochondria-dependent apoptotic pathway.