Bcl2perhe

Bcl2perhe, commonly known as the Bcl-2 family, comprises a group of intracellular regulators of apoptosis that operate primarily at the mitochondrial outer membrane. Members are characterized by Bcl-2 homology (BH) domains and are broadly categorized as antiapoptotic, proapoptotic effector, or proapoptotic BH3-only proteins. Antiapoptotic proteins such as BCL2, BCL-XL (BCL2L1), MCL1, BCL-W (BCL2L2), and BCL2A1 (BFL-1) preserve cell survival by sequestering proapoptotic members. Proapoptotic effectors, Bax and Bak, promote mitochondrial outer membrane permeabilization (MOMP) when activated. BH3-only proteins, including BAD, BIM, BID, PUMA (BBC3) and NOXA (PMAIP1), sense cellular stress and either inhibit antiapoptotic proteins or directly activate Bax/Bak.

In response to cellular stress, BH3-only proteins bind to antiapoptotic Bcl-2 family members, freeing Bax/Bak to oligomerize in the outer mitochondrial membrane, triggering MOMP. This leads to cytochrome c release, apoptosome formation, caspase activation, and programmed cell death. The balance among these family members determines cell fate.

Dysregulation of Bcl2perhe is associated with cancer, neurodegeneration, and immune disorders. Therapies aiming at this axis, such as BH3 mimetics that inhibit antiapoptotic proteins (e.g., venetoclax targeting BCL-2; navitoclax targeting BCL-2/BCL-XL), have clinical use and development ongoing. Resistance can arise via upregulation of MCL-1 or BCL-XL or mutations in Bax/Bak.

Bcl2perhe proteins are evolutionarily conserved and play essential roles in development and tissue homeostasis by regulating the intrinsic apoptotic pathway.