Abstract
Intrinsic apoptosis, the response to intracellular cell death stimuli, is regulated by the interplay of the B-cell lymphoma 2 (Bcl-2) family and their membrane interactions. Bcl-2 proteins mediate a number of processes including development, homeostasis, autophagy, and innate and adaptive immune responses and their dysregulation underpins a host of diseases including cancer. The Bcl-2 family is characterized by the presence of conserved sequence motifs called Bcl-2 homology motifs, as well as a transmembrane region, which form the interaction sites and intracellular location mechanism, respectively. Bcl-2 proteins have been recognized in the earliest metazoans including Porifera (sponges), Placozoans, and Cnidarians (e.g., Hydra). A number of viruses have gained Bcl-2 homologs and subvert innate immunity and cellular apoptosis for their replication, but they frequently have very different sequences to their host Bcl-2 analogs. Though most mechanisms of apoptosis initiation converge on activation of caspases that destroy the cell from within, the numerous gene insertions, deletions, and duplications during evolution have led to a divergence in mechanisms of intrinsic apoptosis. Currently, the action of the Bcl-2 family is best understood in vertebrates and nematodes but new insights are emerging from evolutionarily earlier organisms. This review focuses on the mechanisms underpinning the activity of Bcl-2 proteins including their structures and interactions, and how they have changed over the course of evolution.
Highlights
Apoptosis or programmed death of cells has played a significant role in metazoan evolution and prioritizes the organism over individual cells [1,2]
The genes most closely associated with intrinsic apoptosis are the B-cell lymphoma 2 (Bcl-2) family and have been identified in the basal clades of metazoans, including Porifera, Cnidaria, and Placozoa [4]
The threshold for cell fate is mediated by antagonism between prosurvival and proapoptotic members of the Bcl-2 family [5] and this fundamental interaction is conserved from sponges [6] to man [7]
Summary
Apoptosis or programmed death of cells has played a significant role in metazoan evolution and prioritizes the organism over individual cells [1,2]. The genes most closely associated with intrinsic apoptosis are the B-cell lymphoma 2 (Bcl-2) family and have been identified in the basal clades of metazoans, including Porifera (sponges), Cnidaria (anemones, corals, jellyfish), and Placozoa [4]. In mammals, these genes regulate the integrity of mitochondria where they either initiate the release of apoptogenic factors or prevent this process from occurring (Figure 1). SSiimmpplliiffiieeddaappooppttoossisissscchheemmeesssshhoowwininggththeeroroleleoof f BBccl-l2-2pprrootteeininssiinnaappooppttoossiissiinniittiiaattiioonn ddiiffffeerr bbeettwweeeenn mmaammmmaallss ((aa)) aannddnneemmaattooddeess((bb))..TThheeBBclc-l2-2fafmamiliyly mmeemmbbeerrssaarereininddiciactaetdedfofrorMM. BBccl-l2-2pprorotetieninss(T(aTbalbel1e)1a)rearide eindteinfiteidfiebdy bthyetphreespernecseenocfeuopftoupfotuor fcoounrsecrovnesderlivneedarlisneeqauresnecqeumenoctiefs omr dotoimfs aoirnds ocmomaipnrsiscionmg parbiosiuntg2a0broeusitd2u0erseasniddukesnoawndnkansoBwcln-2asHBocml-o2lHogoym(oBlHog)ym(oBtHif)s m(Foigtiufsre(F2i)g[u7r,e9].
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