Diversity in the intrinsic apoptosis pathway of nematodes

Young, Neil D.; Harris, Tiffany J; Evangelista, Marco; Tran, Sharon; Wouters, Merridee A.; Costa, Tatiana P. Soares da; Kershaw, Nadia J.; Gasser, Robin B.; Smith, Brian J.; Lee, Erinna F.; Fairlie, W. Douglas

doi:10.1038/s42003-020-01208-5

Cited by 4 publications

(16 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, analyses from several genomes (cnidarian, nematode, fly, amphioxus, sea urchin, human) clearly identified three well-defined independent clades of paralogous genes among metazoans, highlighting that Ced-4, Dark and Apaf-1 are not homologous between ecdysozoans and vertebrates 25 . The divergent evolution history of structural actors of the apoptosome platforms confirm functional analyses carried out so far suggesting that caspase structure and interaction differs among taxa and clades 16 .…”

Section: Resultssupporting

confidence: 78%

“…Next, investigation of apoptotic cascade key components from Drosophila and mammals imposed the paradigm that the intrinsic apoptotic “molecular program” is conserved throughout animal evolution 2,4–7 . However, recent researches revealed evolutionary divergences between these models, with major functional implications 15,16 . Based on evolutionarily conserved or divergent features of the cell death machinery among metazoans, we investigated the evolutionary history of several major actors of intrinsic apoptosis.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Intrinsic apoptosis is evolutionarily divergent among metazoans

Krasovec

Qeinnec

Chambon

2021

Preprint

View full text Add to dashboard Cite

Apoptosis is characterised by an analogous set of morphological features1 that depend on a proteolytic multigenic family, the caspases. Each apoptotic signalling pathway involves a specific initiator caspase, upstream of the pathway regulation, which finally converges to common executioner caspases. Intrinsic apoptosis, previously known as the mitochondrial apoptotic pathway, is often considered as ancestral and evolutionary conserved among animals. First identified in the nematode Caenorhabditis elegans, intrinsic apoptosis was next characterised in fruit fly Drosophila melanogaster and mammals. Intrinsic apoptosis depends on the key initiator caspase-9 (named Ced-3 and Dronc in Caenorhabditis and Drosophila, respectively), the activator Apaf-1 and the Bcl-2 multigenic family. Many functional studies have led to a deep characterisation of intrinsic apoptosis based on those classical models. Nevertheless, the biochemical role of mitochondria, the pivotal function of cytochrome c and the modality of caspases activation remain highly heterogeneous and hide profound molecular divergences among apoptotic pathways in animals. Independent of functional approaches, the phylogenetic history of the signal transduction actors, mostly the caspase family, is the Rosetta Stone to shed light on intrinsic apoptosis evolution. Here, after exhaustive research on CARD-caspases, we demonstrate by phylogenetic analysis that the caspase-9, the fundamental key of intrinsic apoptosis, is deuterostomes-specific, while it is the caspase-2 which is ancestral and common to bilaterians. Our analysis of Bcl-2 family and Apaf-1 confirm the high heterogeneity in apoptotic pathways elaboration in animals. Taken together, our results support convergent emergence of distinct intrinsic apoptotic pathways during metazoan evolution.

show abstract

Section: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Intrinsic apoptosis is evolutionarily divergent among metazoans

Krasovec

Qeinnec

Chambon

2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Thus, in both ctenophores and myxozoans, the genes related to MOMP initiated apoptosis appear to have been lost. Other Bilaterians have also lost Bcl-2 family members such as H. miamia , and Clade IV nematode species Meloidogyne , Globodera , and Ditylenchus [ 31 ]; in the case of H. miamia, caspase-7 and caspase-8 genes are present [ 53 ].…”

Section: Resultsmentioning

confidence: 99%

“…Early Bilaterians generally have genes that cluster with the mammalian Bcl-2 family ( Figure 4 b). The absence of Bcl-2 genes in ctenophores, myxozoans, some tunicates, and certain nematodes [ 31 ] suggests Bcl-2 gene loss is not critical to survival, homeostasis, development and multicellularity in these organisms.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, ctenophores appear to have lost the Bcl-2 family and related intrinsic apoptosis genes, as have a number of other early metazoans. We did not identify any higher organism lacking Bcl-2 family genes, though it is known that certain nematodes lack these genes [ 31 ]; a definitive answer is likely to require sampling a broader range of basal metazoan genomes [ 32 ]. Understanding the emergence and evolutionary basis of their action may provide insight into the roles of Bcl-2 proteins normal function and disease.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Metazoans and Intrinsic Apoptosis: An Evolutionary Analysis of the Bcl-2 Family

Suraweera

Banjara

Hinds

et al. 2022

IJMS

View full text Add to dashboard Cite

The B-cell lymphoma-2 (Bcl-2) family is a group of genes regulating intrinsic apoptosis, a process controlling events such as development, homeostasis and the innate and adaptive immune responses in metazoans. In higher organisms, Bcl-2 proteins coordinate intrinsic apoptosis through their regulation of the integrity of the mitochondrial outer membrane; this function appears to have originated in the basal metazoans. Bcl-2 genes predate the cnidarian-bilaterian split and have been identified in porifera, placozoans and cnidarians but not ctenophores and some nematodes. The Bcl-2 family is composed of two groups of proteins, one with an α-helical Bcl-2 fold that has been identified in porifera, placozoans, cnidarians, and almost all higher bilaterians. The second group of proteins, the BH3-only group, has little sequence conservation and less well-defined structures and is found in cnidarians and most bilaterians, but not porifera or placozoans. Here we examine the evolutionary relationships between Bcl-2 proteins. We show that the structures of the Bcl-2-fold proteins are highly conserved over evolutionary time. Some metazoans such as the urochordate Oikopleura dioica have lost all Bcl-2 family members. This gene loss indicates that Bcl-2 regulated apoptosis is not an absolute requirement in metazoans, a finding mirrored in recent gene deletion studies in mice. Sequence analysis suggests that at least some Bcl-2 proteins lack the ability to bind BH3-only antagonists and therefore potentially have other non-apoptotic functions. By examining the foundations of the Bcl-2 regulated apoptosis, functional relationships may be clarified that allow us to understand the role of specific Bcl-2 proteins in evolution and disease.

show abstract

Molecular dynamics studies of CED‐4/CED‐9/EGL‐1 ternary complex reveal CED‐4 release mechanism in the linear apoptotic pathway of Caenorhabditis elegans

Reddy

Sankararamakrishnan

2023

Proteins

View full text Add to dashboard Cite

Many steps in programmed cell death are evolutionarily conserved across different species. The Caenorhabditis elegans proteins CED-9, CED-4 and EGL-1 involved in apoptosis are respectively homologous to anti-apoptotic Bcl-2 proteins, Apaf-1 and the "BH3-only" pro-apototic proteins in mammals. In the linear apoptotic pathway of C. elegans, EGL-1 binding to CED-9 leads to the release of CED-4 from CED-9/ CED-4 complex. The molecular events leading to this process are not clearly elucidated. While the structures of CED-9 apo, CED-9/EGL-1 and CED-9/CED-4 complexes are known, the CED-9/CED-4/EGL-1 ternary complex structure is not yet determined. In this work, we modeled this ternary complex and performed molecular dynamics simulations of six different systems involving CED-9. CED-9 displays differential dynamics depending upon whether it is bound to CED-4 and/or EGL-1. CED-4 exists as an asymmetric dimer (CED4a and CED4b) in CED-9/CED-4 complex. CED-4a exhibits higher conformational flexibility when simulated without CED-4b. Principal Component Analysis revealed that the direction of CED-4a's winged-helix domain motion differs in the ternary complex. Upon EGL-1 binding, majority of non-covalent interactions involving CARD domain in the CED-4a-CED-9 interface have weakened and only half of the contacts found in the crystal structure between α/β domain of CED4a and CED-9 are found to be stable. Additional stable contacts in the ternary complex and differential dynamics indicate that winged-helix domain may play a key role in CED-4a's dissociation from CED-9. This study has provided a molecular level understanding of potential intermediate states that are likely to occur when CED-4a is released from CED-9.

show abstract

Diversity in the intrinsic apoptosis pathway of nematodes

Cited by 4 publications

References 68 publications

Intrinsic apoptosis is evolutionarily divergent among metazoans

Intrinsic apoptosis is evolutionarily divergent among metazoans

Metazoans and Intrinsic Apoptosis: An Evolutionary Analysis of the Bcl-2 Family

Molecular dynamics studies of CED‐4/CED‐9/EGL‐1 ternary complex reveal CED‐4 release mechanism in the linear apoptotic pathway of Caenorhabditis elegans

Contact Info

Product

Resources

About