Surprising complexity of the ancestral apoptosis network

Burnham Institute for Medical Research, North Torrey Pines Road, La Jolla, CA 92037, USA.
Genome biology (Impact Factor: 10.81). 02/2007; 8(10):R226. DOI: 10.1186/gb-2007-8-10-r226
Source: PubMed

ABSTRACT Apoptosis, one of the main types of programmed cell death, is regulated and performed by a complex protein network. Studies in model organisms, mostly in the nematode Caenorhabditis elegans, identified a relatively simple apoptotic network consisting of only a few proteins. However, analysis of several recently sequenced invertebrate genomes, ranging from the cnidarian sea anemone Nematostella vectensis, representing one of the morphologically simplest metazoans, to the deuterostomes sea urchin and amphioxus, contradicts the current paradigm of a simple ancestral network that expanded in vertebrates.
Here we show that the apoptosome-forming CED-4/Apaf-1 protein, present in single copy in vertebrate, nematode, and insect genomes, had multiple paralogs in the cnidarian-bilaterian ancestor. Different members of this ancestral Apaf-1 family led to the extant proteins in nematodes/insects and in deuterostomes, explaining significant functional differences between proteins that until now were believed to be orthologous. Similarly, the evolution of the Bcl-2 and caspase protein families appears surprisingly complex and apparently included significant gene loss in nematodes and insects and expansions in deuterostomes.
The emerging picture of the evolution of the apoptosis network is one of a succession of lineage-specific expansions and losses, which combined with the limited number of 'apoptotic' protein families, resulted in apparent similarities between networks in different organisms that mask an underlying complex evolutionary history. Similar results are beginning to surface for other regulatory networks, contradicting the intuitive notion that regulatory networks evolved in a linear way, from simple to complex.

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Available from: Christian M. Zmasek, Sep 28, 2015
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    • "In pro-apoptotic group, the effector proteins (BAX and BOK) contain BH domains 1e3 and a TM domain whereas, BH3-only proteins (BAD and BID) harbor only the BH3 domain and lacked in TM domain [16e18]. BCL-2 family genes have been reported in vertebrates including fish [19], amphibian [20] and mammal [21] and in invertebrates including mollusk [22], sea urchin [23], planarian [24], sea anemone [25] and sponge [26]. Recently we have reported bioinformatics characterization and gene expression studies on antiapoptotic gene BCL-2from striped murrel [27]. "
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    ABSTRACT: In this study, we have reported a molecular characterization of the first B cell lymphoma-2 (BCL-2) related ovarian killer protein (BOK) from freshwater prawn Macrobrachium rosenbergii (Mr). BOK is a novel pro-apoptotic protein of the BCL-2 family that entails in mediating apoptosis to remove cancer cells. A cDNA sequence of MrBOK was identified from the prawn cDNA library and its full length was obtained by internal sequencing. The coding region of MrBOK yields a polypeptide of 291 amino acids. The analysis revealed that MrBOK contains a transmembrane helix at V(261)-L(283) and a putative BCL-2 family domain at V(144)-W(245). MrBOK also possessed four putative BCL-2 homology domains including BH1, BH2, BH3 and weak BH4. The BH3 contains 21 binding sites and among them five residues are highly conserved with the aligned BOK proteins. The homology analysis showed that MrBOK shared maximum similarity with the Caligus rogercresseyi BOK A. The topology of the phylogenetic tree was classified into nine sister groups which includes BOK, BAK, BAX, BAD, BCL-2, BCL-XL, NR13 and MCL members. The BOK protein group further sub-grouped into vertebrate and invertebrate BOK, wherein MrBOK located within insect monophyletic clad of invertebrate BOK. The secondary structural analysis showed that MrBOK contains 11 α-helices (52.2%) which are connected over random coils (47.7%). The 3D structure of MrBOK showed three central helices (α6, α7 and α8) which formed the core of the protein and are flanked on one side by α1, α2 and α3, and on the other side by α4, α5 and α11. MrBOK mRNA is expressed most abundantly (P < 0.05) in ovary compared to other tissues taken for analysis. Hence ovary was selected to study the possible roles of MrBOK mRNA regulation upon bacterial (Aeromonas hydrophila and Vibrio harveyi) and viral [white spot syndrome virus (WSSV) and M. rosenbergii nodovirus] infection. During bacterial and viral infection, the highest MrBOK mRNA transcription was varied at different time points. In bacterial infected ovary tissue, the highest mRNA expression was at 24 h post-infection, whereas in viral infection, the expression was highest at 48 h post-infection. Thus we can conclude that MrBOK functions as an apoptotic protein in intracellular programmed cell-death pathway to counteract the anti-apoptotic proteins released by bacterial and viral pathogens at the time of infection. This is the first study that emphasizes the importance of BOK during bacterial and viral infection in crustacean. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Fish &amp Shellfish Immunology 05/2015; 45(2). DOI:10.1016/j.fsi.2015.04.031 · 2.67 Impact Factor
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    • "The evolution of the apoptotic pathway does not seem to be a linear process of complexity increase but is inherently dynamic , including lineage-specific gene losses and expansions and the emergence/reemergence of similar proteins [151]. In this context, the apparent simplicity of apoptosis in nematodes and insects might not be the ancestral state but, most likely, a result of more recent simplifications [152]. High complexity levels have been described in the apoptotic network of Mollusca, in which certain key components (p53, Bcl-2 family proteins, BI-1 and PDRD proteins) are more related to those of vertebrates and others (initiator caspases and Dff-A protein) are more related to invertebrate components [28] [54] [109] [119] [147]. "
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    ABSTRACT: Apoptosis is a type of programmed cell death that produces changes in cell morphology and in biochemical intracellular processes without inflammatory reactions. The components of the apoptotic pathways are conserved throughout evolution. Caspases are key molecules involved in the transduction of the death signal and are responsible for many of the biochemical and morphological changes associated with apoptosis. Nowadays, It is known that caspases are activated through two major apoptotic pathways (the extrinsic or death receptor pathway and the intrinsic or mitochondrial pathway), but there are also evidences of at least other alternative pathway (the perforin/granzyme pathway). Apoptosis in mollusks seems to be similar in complexity to apoptosis in vertebrates but also has unique features maybe related to their recurrent exposure to environmental changes, pollutants, pathogens and also related to the sedentary nature of some stages in the life cycle of mollusks bivalves and gastropods. As in other animals, apoptotic process is involved in the maintenance of tissue homeostasis and also constitutes an important immune response that can be triggered by a variety of stimuli, including cytokines, hormones, toxic insults, viruses, and protozoan parasites. The main goal of this work is to present the current knowledge of the molecular mechanisms of apoptosis in mollusks and to highlight those steps that need further study. Copyright © 2015. Published by Elsevier Ltd.
    Fish &amp Shellfish Immunology 04/2015; 46(1). DOI:10.1016/j.fsi.2015.03.038 · 2.67 Impact Factor
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    • "It was further explained that some apoptotic mechanisms such as caspase-independent cell death in C. elegans and Drosophila are more similar to that of vertebrates but different from mollusks. Different BCL-2 family homologs have been identified from other invertebrates such as sea urchin [13], planarian Schmidtea mediterranea [14], sea anemone [15], and sponge [16]. In mollusks, several studies have been overviewed on apoptosis related immune "
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    ABSTRACT: Apoptosis based immune responses are important component of host defense in mollusks. In this study, we have identified two novel molluscan BCL-2 cDNAs from Manila clam, Ruditapes philippinarum and named as RpBCL-2A and RpBCL-2B. There were four and three highly conserved BCL-2 homology (BH) regions in RpBCL-2A and RpBCL-2B, respectively suggesting these two genes could be different isoforms of anti-apoptotic BCL-2 family. Phylogenetic results revealed that Manila clam BCL-2 genes were clustered closely with invertebrate BCL-2 members. It gives evidence of their common origin and conserved features of invertebrate BCL-2 family. RpBCL-2A and 2B were expressed in tissue specific manner showing the highest and lowest level of expression in gills and hemocytes, respectively. However there was no clear expression profile difference between two genes. After Vibrio tapetis challenge, transcriptional responses of RpBCL-2A and RpBCL-2B were induced in gills and hemocytes with high variation that could be due to effects of immune reactions of other host defense molecules.
    Fish &amp Shellfish Immunology 04/2013; 34(6). DOI:10.1016/j.fsi.2013.03.366 · 2.67 Impact Factor
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