When an apoptotic stimulus triggers the intrinsic pathway, the pro-apoptotic effector Bcl2 family proteins become activated and aggregate to form oligomers in the mitochondrial outer membrane, inducing the release of cytochrome c and other intermembrane proteins by an unknown mechanism (Figure 18–9). In mammalian cells, Bax and Bak are the main effector Bcl2 family proteins, and at least one of them is required for the intrinsic pathway of apoptosis to operate: mutant mouse cells that lack both proteins are resistant to all pro-apoptotic signals that normally activate this pathway. Whereas Bak is bound to the mitochondrial outer membrane even in the absence of an apoptotic signal, Bax is mainly located in the cytosol and translocates to the mitochondria only after an apoptotic signal activates it. As we discuss below, the activation of Bax and Bak usually depends on activated pro-apoptotic BH3-only proteins.
The anti-apoptotic Bcl2 family proteins such as Bcl2 itself and BclXL are also located on the cytosolic surface of the outer mitochondrial membrane, where they help prevent inappropriate release of intermembrane proteins. The antiapoptotic Bcl2 family proteins inhibit apoptosis mainly by binding to and inhibiting pro-apoptotic Bcl2 family proteins—either on the mitochondrial membrane or in the cytosol. On the outer mitochondrial membrane, for example, they bind to Bak and prevent it from oligomerizing, thereby inhibiting the release of cytochrome c and other intermembrane proteins. There are at least five mammalian anti-apoptotic Bcl2 family proteins, and every mammalian cell requires at least one to survive. Moreover, a number of these proteins must be inhibited for the intrinsic pathway to induce apoptosis; the BH3-only proteins mediate the inhibition.
The BH3-only proteins are the largest subclass of Bcl2 family proteins. The cell either produces or activates them in response to an apoptotic stimulus, and they are thought to promote apoptosis mainly by inhibiting anti-apoptotic Bcl2 family
Figure 18–8 The three classes of Bcl2 family proteins. Note that the Bh3 domain is the only Bh domain shared by all Bcl2 family members; it mediates the direct interactions between pro-apoptotic and anti-apoptotic family members.
Figure 18–9 The role of pro-apoptotic effector Bcl2 family proteins (mainly Bax and Bak) in the release of mitochondrial intermembrane proteins in the intrinsic pathway of apoptosis. When activated by an apoptotic stimulus, the effector Bcl2 family proteins aggregate on the outer mitochondrial membrane and release cytochrome c and other proteins from the intermembrane space into the cytosol by an unknown mechanism.
proteins. Their BH3 domain binds to a long hydrophobic groove on anti-apoptotic Bcl2 family proteins, neutralizing their activity. This binding and inhibition enables the aggregation of Bax and Bak on the surface of mitochondria, which triggers the release of the intermembrane mitochondrial proteins that induce apoptosis (Figure 18–10). Some BH3-only proteins may bind directly to Bax and Bak to help stimulate their aggregation.
BH3-only proteins provide the crucial link between apoptotic stimuli and the intrinsic pathway of apoptosis, with different stimuli activating different BH3only proteins. Some extracellular survival signals, for example, block apoptosis by inhibiting the synthesis or activity of certain BH3-only proteins (see Figure 18–12B). Similarly, in response to DNA damage that cannot be repaired, the tumor suppressor protein p53 accumulates (discussed in Chapters 17 and 20) and activates the transcription of genes that encode the BH3-only proteins Puma and Noxa. These BH3-only proteins then trigger the intrinsic pathway, thereby eliminating a potentially dangerous cell that could otherwise become cancerous.