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  • Review Article
  • Published:

The role of BH3-only proteins in the immune system

Nature Reviews Immunology volume 5, pages 189–200 (2005)Cite this article

Key Points

  • 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.

Abstract

Programmed cell death — also known as apoptosis — has a crucial role in the immune system of mammals and other animals. It removes useless cells and potentially dangerous cells, including lymphocytes, and is involved in killing pathogen-infected or damaged cells. Defects in this process have been found to cause or contribute to diseases of the immune system, including immunodeficiency, autoimmunity, lymphoma and leukaemia. This review describes BH3-only proteins, a pro-apoptotic subgroup of the BCL-2 family, and their role in the development and function of the immune system.

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Figure 1: Life-and-death decisions during B- and T-cell development.
Figure 2: General model of signalling pathways that mediate apoptosis.
Figure 3: The mammalian BCL-2-family members.
Figure 4: Models for interaction between BH3-only proteins, BAX/BAK-like proteins and pro-survival BCL-2-family members in signalling in apoptosis.
Figure 5: Different apoptotic stimuli trigger apoptosis through activation of different BH3-only proteins.
Figure 6: Mechanisms for BIM activation in lymphoid cells.

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Acknowledgements

I thank J. Adams, S. Cory, D. Vaux, J. Miller, D. Metcalf, A. Harris, P. Bouillet, D. Huang, H. Puthalakath, L. O'Reilly, S. Bath, A. Villunger, C. Scott, L. O'Connor, K. Newton, V. Marsden, L. Coultas, E. Michalak, P. Kelly and E. Naik for all of their work and for many fruitful discussions. I apologize to the many scientists whose excellent work was not cited directly in the text but only referred to indirectly through reviews. Work in my laboratory is supported by fellowships and grants from the National Health and Medical Research Council (Australia), the Leukemia & Lymphoma Society (United States), the National Institutes of Health (United States), the Juvenile Diabetes Research Foundation International (United States), The Cancer Council Victoria (Australia) and the Cancer Research Institute (United States).

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    Andreas Strasser

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DATABASES

Entrez Gene

BAD

BAK

BAX

BCL-2

BID

BIK

BIM

BMF

HRK

NOXA

PUMA

Glossary

NEGATIVE SELECTION IN THE THYMUS

The deletion of self-reactive thymocytes. Thymocytes expressing T-cell receptors that strongly bind self-peptide bound to self-MHC molecules undergo apoptosis in response to the signalling generated by high-affinity binding.

TUMOUR-NECROSIS-FACTOR-RECEPTOR FAMILY

(TNFR family). A family of cell-surface receptors that binds members of the TNF-ligand family. The receptors all contain cysteine-rich extracellular regions that are involved in ligand binding.

DEATH DOMAIN

A protein–protein interaction domain found in many proteins that are involved in signalling and apoptosis.

LYMPHADENOPATHY

Enlargement of the lymph nodes.

BCL-2 HOMOLOGY DOMAIN

(BH domain). These domains are regions of amino-acid sequence and structural similarity in members of the B-cell lymphoma 2 (BCL-2) family. These regions are involved in interactions between pro- and anti-apoptotic members of this family.

POSITIVE SELECTION

The process in the thymus that selects thymocytes expressing T-cell receptors (TCRs) that can interact weakly with self-MHC molecules. This weak interaction generates differentiation and survival signals in these lymphocytes, the TCRs of which later recognize foreign peptides bound to self-MHC. Positive selection establishes the MHC-restricted T-cell repertoire.

IMMUNOLOGICAL MEMORY

A consequence of the ability of the adaptive arm of the immune system to respond more rapidly and efficiently after a primary immune response to a subsequent challenge with the same pathogen or experimentally administered antigen. Immunological memory is maintained by long-term survival of antigen-specific B and T cells.

ASPARTIC-ACID-SPECIFIC CYSTEINE PROTEASES

A family of enzymes that has a cysteine residue in the active site and cleaves substrates after an aspartic acid residue. Members of this family are also known as caspases. Many of them are involved in apoptosis, but some (for example, caspase-1) are also required for processing of certain cytokines (such as interleukin-1β and interleukin-18).

DEATH EFFECTOR DOMAIN

(DED). A domain that is found in certain initiator caspases (for example, mammalian caspase-8) and their adaptor protein FADD. This domain mediates protein–protein interactions.

CASPASE-RECRUITMENT DOMAIN

(CARD). A domain that is found in certain initiator caspases (for example, mammalian caspase-9) and their adaptor proteins (for example, APAF1). This domain mediates protein–protein interactions.

APOPTOSOME

An apoptotic-protein complex formed by the interaction of APAF1 (apoptotic-protease-activating factor 1), cytochrome c and dATP with pro-caspase-9. Complex formation leads to the cleavage and activation of caspase-9, which activates caspase-3 and other effector caspases, leading to cell death.

p53

A tumour suppressor that is found to be mutated in ∼50% of all human cancers. The p53 protein is a transcription factor that is activated by damage to DNA, anoxia, expression of certain oncogenes, and several other stress stimuli. Target genes activated by p53 regulate cell-cycle arrest, apoptosis, cell senescence and DNA repair.

λ-PHAGE EXPRESSION LIBRARY

A library that is used to find binding partners for known proteins. Cellular proteins are expressed from a λ-phage vector in infected Escherichia coli, and probing is carried out using tagged (for example, with 32P) 'bait' protein, usually produced in E. coli.

YEAST TWO-HYBRID LIBRARY

A library that is used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins: one protein is fused to the DNA-binding domain of GAL4, and the other is fused to the activation domain of GAL4. The two proteins are expressed together in yeast, and if they interact, the resulting complex then drives the expression of a reporter gene, commonly β-galactosidase.

CALCIUM IONOPHORE

A drug that promotes calcium flux into cells.

ETOPOSIDE

A chemotherapeutic drug that is widely used. It is a semi-synthetic podophyllotoxin derived from the root of Podophyllum peltatum (may apple). It induces single-stranded DNA breaks, as well as DNA damage, through inhibition of DNA topoisomerase II.

GLUCOCORTICOIDS

A group of compounds that belongs to the corticosteroid family. These compounds can be naturally produced (hormones) or synthetic. They affect metabolism and have anti-inflammatory and immunosuppressive effects. Some synthetic glucocorticoids (for example, dexamethasone) are used as chemotherapeutic drugs.

UBIQUITYLATION

The attachment of the small protein ubiquitin to lysine residues that are present in other proteins. This tags these proteins for rapid cellular degradation.

14-3-3 SCAFFOLD PROTEINS

A family of conserved proteins that is present in all eukaryotic organisms. These proteins are involved in diverse cellular processes, such as apoptosis and stress, as well as in intracellular signalling and cell-cycle regulation. They function as adaptors in protein interactions and can regulate protein localization and enzymatic activity. Approximately 100 binding partners have been reported for the 14-3-3 proteins.

Eμ-MYC TRANSGENE

A transgene construct that subjugates expression of the proto-oncogene MYC (which promotes cell cycling) under the control of the immunoglobulin heavy-chain gene enhancer Eμ. This drives expression of the MYC oncogene in B cells and causes development of pre-cursor (pre)-B-cell- and B-cell lymphoma in mice.

HAPLOINSUFFICIENT

A condition caused when loss of a single allele of a gene causes a noticeable phenotypic abnormality. This indicates that the levels of the corresponding protein are limiting under normal circumstances.

BCR–ABL KINASE

An oncogenic kinase that is formed by the fusion of the Abelson leukaemia-virus protein (ABL) and the breakpoint-cluster region (BCR). This occurs as a consequence of the t(9; 22) chromosomal translocation (known as the Philadelphia chromosome), which is found in most cases of chronic myeloid leukaemia (CML). The BCR–ABL kinase is the target of the anticancer drug imatinib (Gleevec), which has proven highly successful in the treatment of CML.

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Strasser, A. The role of BH3-only proteins in the immune system. Nat Rev Immunol 5, 189–200 (2005). https://doi.org/10.1038/nri1568

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