A Unified Model of Mammalian BCL-2 Protein Family Interactions at the Mitochondria

作者：Llambi Fabien; Moldoveanu Tudor; Tait Stephen W G; Bouchier Hayes Lisa; Temirov Jamshid; McCormick Laura L; Dillon Christopher P; Green Douglas R^*

来源：Molecular Cell, 2011, 44(4): 517-531.

DOI：10.1016/j.molcel.2011.10.001

During apoptosis, the BCL-2 protein family controls mitochondrial outer membrane permeabilization (MOMP), but the dynamics of this regulation remain controversial. We employed chimeric proteins composed of exogenous BH3 domains inserted into a tBID backbone that can activate the proapoptotic effectors BAX and BAK to permeabilize membranes without being universally sequestered by all antiapoptotic BCL-2 proteins. We thus identified two "modes" whereby prosurvival BCL-2 proteins can block MOMP, by sequestering direct-activator BH3-only proteins ("MODE 1") or by binding active BAX and BAK ("MODE 2"). Notably, we found that MODE 1 sequestration is less efficient and more easily derepressed to promote MOMP than MODE 2. Further, MODE 2 sequestration prevents mitochondrial fusion. We provide a unified model of BCL-2 family function that helps to explain otherwise paradoxical observations relating to MOMP, apoptosis, and mitochondrial dynamics.

• 出版日期2011-11-18