The role of BH3-only proteins in the immune system

Abstract

BH3-only (B-cell lymphoma 2 (BCL-2)-homology domain 3 only) proteins are a pro-apoptotic subgroup of the BCL-2 family. They share with each other and the rest of the BCL-2 family only the short (9–16 amino acid) BH3 region. The BH3 domain of BH3-only proteins is required for the ability of these proteins to bind BCL-2-like pro-survival proteins and to trigger apoptosis. BH3-only proteins are essential for the initiation of programmed cell death and stress-induced apoptosis in species as distantly related as nematodes and mice. Mammals have at least eight BH3-only proteins, and these are activated by different apoptotic stimuli. There is also evidence for cell-type-restricted functions of mammalian BH3-only proteins. BH3-only proteins trigger apoptosis by a mechanism that requires BAX- (BCL-2-associated X protein)/BAK (BCL-2-antagonist/killer)-like members of the multi-BH-domain pro-apoptotic subgroup of the BCL-2 family. The BH3-only protein BIM (BCL-2-interacting mediator of cell death) is essential for lymphocyte homeostasis, for negative selection of autoreactive T and B cells and for shut-down of immune responses. The BH3-only protein PUMA (p53-upregulated modulator of apoptosis), and to a lesser extent NOXA, is required for DNA-damage-induced apoptosis, which is mediated by the tumour-suppressor protein p53. The BH3-only protein BID (BH3-interacting-domain death agonist) is activated by caspase-mediated proteolysis and has a cell-type-restricted role in death-receptor-induced apoptosis. Defects in BH3-only proteins can cause autoimmune disease or cancer, particularly in combination with mutations that dysregulate cell-cycle control. Loss of BIM prevents the immunodeficiency and the other degenerative disorders that are caused by BCL-2 deficiency, and it partially restores B- and T-cell numbers and enhances immune responses in mice that lack the α-chain of the interleukin-7 receptor. BH3-only proteins, in particular PUMA and BIM, are required for the apoptosis that is induced in lymphocytes and fibroblasts by γ-rays or by certain chemotherapeutic drugs, indicating that these proteins have a role in anticancer therapy of human malignancies.