Role of T cell death in maintaining immune tolerance during persistent viral hepatitis

Figure 6 Models for intrinsic cell death. A: Direct activation model postulates Bcl-2 interacting mediator (Bim) is required for activating Bax and Bak. Anti-apoptotic proteins inhibit BH3-only proteins to suppress apoptosis, but not Bax or Bak. Replacement of Bim to sensitizer BH3-proteins from the anti-apoptotic proteins occurs to promote apoptosis; B: The displacement model proposes that anti-apoptotic proteins for cell survival must sequester constitutively active Bax and Bak in cells. Bim inhibits their respective anti-apoptotic proteins by playing sensitizer role to promote apoptosis; C: Embedded together model highlights the active role of the membrane, which is not defined in direct activation model and displacement model. Bcl-2 family proteins insert into and change their conformations that dictate their functions at the membrane. Sensitizer BH3-only proteins relocate the activator BH3-only proteins and Bax/Bak from the anti-apoptotic proteins to endorse apoptosis. Activator BH3-only proteins recruit Bax to the membrane to induce mitochondrial outer membrane permeabilization and apoptosis. These reversible interactions are directed by equilibrium constants that are depended on the concentrations and interactions of the proteins with each other and with membranes.