BH3‐Only Proteins


The deregulation of programmed cell death, apoptosis, is a major contributor to the development of diseases, including cancer or autoimmunity, and can impair the response of transformed cells to therapy. The Bcl‐2 family of proteins includes critical regulators of the intrinsic apoptosis pathway. BH3 (Bcl‐2 homologous 3)‐only proteins are proapoptotic members that share with each other and the wider Bcl‐2 family only the ‘BH3 domain’. This short stretch of about 16 amino acids is necessary for protein–protein interaction that is critical for their apoptosis‐inducing capacity. BH3‐only proteins promote cell death by regulating activation of Bax and Bak, in a cell‐type and stimulus‐specific manner. Studies of gene‐targeted mice that lack two or more BH3‐only proteins have helped to unravel the overlapping functions of these apoptosis initiators. With the dawn of CRISPR/Cas9 gene‐editing technologies, this strategy was taken even further, opening up allegedly answered questions again, at least at the cellular level. BH3 mimetics were recently approved for the treatment of patients suffering from cancer and it can be anticipated that these drugs make second use to treat autoimmunity and ageing‐related disorders in the future.

Key Concepts

  • The ‘Bcl‐2‐regulated’ (also called ‘intrinsic’ or ‘mitochondrial’) apoptotic pathway is triggered by developmental cues or a broad range of cell stressors (e.g. growth factor deprivation and γ‐irradiation) and is regulated by the interplay of the pro‐ and antiapoptotic members of the Bcl‐2 family of proteins controlling integrity of the outer mitochondrial membrane (OMM).
  • The survival versus death fate of a cell is decided not only by the relative levels of pro‐ and antiapoptotic Bcl‐2 family members, but also depends on their ‘activation status’, frequently imposed by different posttranslational modifications on these proteins.
  • Abnormal cell survival during establishment and maintenance of immune‐(self)‐tolerance as well as defects in apoptosis signalling at the end of an immune response may lead to neoplastic transformation and tumourigenesis.
  • The Bcl‐2 family consists of three subgroups of proteins that can be differentiated based on amino acid sequence, 3D structure and function. Bcl‐2, Bcl‐xL, Bcl‐w, Bcl‐B, Mcl‐1 and A1 are essential for cell survival, with cell‐type‐specific expression, while Bcl‐B is found active only in humans. The two other, proapoptotic, subfamilies encompass the multi‐BH domain Bcl‐2 family members Bax, Bak and Bok as well as the BH3‐only protein subfamily members Bad, Bid, Bik/Nbk/Blk, Hrk/DP5, Bim/Bod/Bcl2L11, Noxa/Pmaip, Bmf and Puma/Bbc3. The BH3‐only proteins are critical activators of the effector phase of the intrinsic death pathway, while Bax and Bak act as executers of apoptosis by initiating mitochondrial outer membrane permeabilisation (MOMP). The role of Bok in this group remains to be clarified in full.
  • Both Puma and Noxa, apoptosis initiators that can be transcriptionally activated by p53 in response to DNA damage or oncogenic stress, can act as tumour suppressors in their own right, particularly in the context of an oncogenic lesion that subverts cell cycle control. Yet, in most circumstances tested, Puma appears more effective, suggesting roles for Noxa outside the p53 response.
  • Bid functions as the link between the ‘death receptor’ and the ‘Bcl‐2‐regulated’ apoptotic pathways by causing an amplification of the caspase cascade that leads to cell destruction. Remarkably, Bid is critical for Fas ‘death receptor’‐induced apoptosis in certain cell types, such as hepatocytes, but dispensable in others, including lymphoid cells. Additional roles of Bid, downstream of other proteases, have been suggested.
  • Bim, the most studied BH3‐only protein, is critical for many physiologic and pathologic cell death processes and is a principal regulator of homeostasis in the lymphoid and myeloid compartment. Bim is crucial for the negative selection of autoreactive immature T‐ and B‐lymphoid cells and for growth factor deprivation‐induced apoptosis of many cell types. Loss of BIM in certain human cancers substantiates its role as a tumour suppressor and ample data supports a key role in anticancer therapy.
  • Additional BH3‐only proteins such as Bmf, Bad, Hrk and Bik are less well studied and poorly understood. Available data suggests that they support the key effectors Bim, Puma or Bid in potentiating cell killing in a cell‐type and stimulus‐dependent manner. Functions outside canonical apoptosis signalling remain plausible.
  • BH3‐only proteins have a crucial function in chemotherapeutic drug‐induced killing of tumour cells and their loss is frequently associated with resistance to anticancer therapy. Some proteins are equally important in killing autoreactive immune cells or can become aberrantly activated in chronic inflammatory or degenerative disorders, contributing to diverse pathologies.
  • Mimicking BH3‐only proteins represents a promising strategy for enhancing the effects of conventional anticancer therapy and for treating autoimmune diseases, whereas the blockade of these proteins may be beneficial in the management of certain degenerative diseases that are characterised by abnormal killing of cells that should be kept alive.

Keywords: BH3‐only; apoptosis; Bcl‐2; mitochondria; BH3‐mimetics

Figure 1. Two distinct mammalian apoptotic pathways exist – ‘death receptor’ (‘extrinsic’) and ‘Bcl‐2‐regulated’ (‘mitochondrial’ or ‘intrinsic’) apoptosis signalling. Each activates different initiator caspases, but converges at the level of effector caspases. The ‘Bcl‐2‐regulated’ apoptotic pathway is triggered by developmental cues or a broad range of cell stressors (e.g. growth factor deprivation and γ‐irradiation) and is regulated by the interplay of the pro‐ and antiapoptotic members of the Bcl‐2 family of proteins.
Figure 2. The Bcl‐2 protein family consists of three subgroups that can be differentiated on the basis of amino acid sequence, 3D structure and function. The prosurvival members, Bcl‐2, Bcl‐xL, Bcl‐w (Bcl‐B), Mcl‐1 and A1, share four conserved Bcl‐2 homologous (BH) domains and are essential for cell survival, with cell‐type‐specific expression. Two subfamilies encompass the apoptosis‐promoting Bcl‐2 family members: the multi‐BH domain proapoptotic subfamily members Bax, Bak and Bok, which are critical for the execution phase of apoptosis, and the BH3‐only subfamily members Bad, Bid, Bik/Nbk/Blk, Hrk/DP5, Bim/Bod/Bcl2L11, Noxa, Bmf and Puma/Bbc3, which are essential for initiation of apoptosis.
Figure 3. Different apoptotic stimuli activate different BH3‐only proteins via distinct signalling pathways. (a) Some death stimuli activate predominantly one BH3‐only protein. (b) Other death stimuli appear to elicit cell‐type‐specific induction of an array of BH3‐only proteins. This may reflect the wiring of the particular cell type, the availability of particular BH3‐only proteins or may reflect the requirement for combinatorial signalling through multiple BH3‐only proteins to allow blockade of all prosurvival Bcl‐2 family members present in a particular cell type.
Figure 4. Two competing models have been proposed to explain how BH3‐only proteins activate Bax/Bak to unleash the downstream effector phases of apoptosis. According to the ‘direct model’, in healthy cells, certain so‐called direct activator BH3‐only proteins (particularly Bid, Bim and possibly Puma) are kept in check by binding to the prosurvival Bcl‐2 family members. Apoptotic stimuli induce the so‐called indirect activator BH3‐only proteins (e.g. Bad, Bik and Bmf), which by binding to the prosurvival Bcl‐2 family members unleash Bid, Bim and Puma, thereby allowing them to bind and directly activate (orange) Bax and Bak from an inactive state (brown). According to the ‘indirect model’, in healthy cells Bax and Bak are kept in an inactive state (brown) by binding to the prosurvival Bcl‐2 family members. Apoptotic stimuli activate BH3‐only proteins (in a cell death stimulus‐ and cell‐type‐specific manner). By binding to the prosurvival Bcl‐2 family members, the BH3‐only proteins cause release and activation of Bax and Bak (orange) indirectly. According to this model, for a cell to be committed to undergo apoptosis, all prosurvival Bcl‐2 family members present must be neutralised by BH3‐only proteins. It is important to note that BH3‐only proteins differ in their potency to trigger apoptosis and this is due to their differences in binding affinities for the different prosurvival Bcl‐2 family members. Bim, Puma and Bid bind all (or most) these proteins with high affinity. In contrast, Bad only binds to Bcl‐2, Bcl‐xL and Bcl‐w, whereas Noxa only binds to Mcl‐1 and A1.


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Further Reading

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Tuzlak, Selma, and Villunger, Andreas(Nov 2016) BH3‐Only Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021569.pub2]