TransDeath Consortium Research Summary
Programmed cell death (PCD) is normally invoked during development and immunity, but inappropriate PCD is associated with pathologies including cancer and degenerative diseases. Conserved genes controlling apoptosis, a type of PCD dependent upon caspase proteinases, were first identified in the model organism C. elegans. Biomedical research has established related mammalian apoptotic pathways. However, phylogenetically conserved PCD types other than apoptosis exist in animal and non-animal cells. The TransDeath project focuses on cellular and molecular events in these less well known cell death types. Thus, the project broadens the experimental net to catch PCD regulators by comparative research on diverse organisms that each may be uniquely suited to unravel a type of conserved PCD process. The main approach is across the eukaryotic kingdom, aiming at understanding these types of cell death in humans. TransDeath thereby produces knowledge on genes and biochemical processes that regulate PCD in different organisms. Furthermore, the project applies such knowledge to develop strategies and targets for human disease therapy. Specific TransDeath objectives include:
- Characterize the diversity of genes & biochemicals controlling PCD of diverse types
- Functionally compare these genes & biochemicals between organisms
- Derive genetic & functional models of PCD evolution
- Test genes & biochemicals on PCD related to human normal function and disease
Background & Approach
According to current understanding, several functionally and mechanistically different forms of PCD exist including apoptosis, autophagy, and necrosis. The functional relationships among these types of cell death have not been elucidated in any species, although they can be detected in non-mammalian models including yeast. The first apoptotic regulatory genes were identified in C. elegans, work that received a 2003 Nobel Prize. Apoptosis is controlled by multiple pathways including extrinsic signaling via death receptors, and by intrinsic pathways involving the mitochondria and endoplasmatic reticulum. These inputs activate proteolytic caspase cascades and subsequent cell death. Pro- and anti-apoptotic Bcl-2 family members are important in controlling mitochondrial signals including cytochrome c whose association with the downstream regulator Apaf-1 and procaspase-9 forms the apoptosome that mediates caspase activation.
Although homologs the apoptotic machinery are not found in plants and lower eukaryotes, comparative phylogenetic analysis of the domains conserved in these proteins indicates that they existed in the common ancestor of animals, plants, and fungi. These ancient domains were, and in some cases still are, components of ancestral signaling pathways for responses to pathogens and stresses including starvation and DNA damage. A goal of TransDeath is to understand the mechanistic relations between extant PCD programs in different organisms. For example, plant leaves senesce at the end of growth seasons. How is this developmental form of PCD related to the more rapid PCD induced during the plant hypersensitive response to pathogens? Similarly, how may these forms of PCD be related to autophagic processes in animals or in fungi and molds that induce PCD during incompatible mating interactions, or the development of reproductive structures? Lastly, how are apoptosis or autophagy related to PCD in unicellular yeasts in which it may have evolved as an altruistic defence of clonal populations?
The work plan aims to define, phenomenologically and molecularly, distinct types of cell death using models appropriate for each type of death. It then aims to extract, from a comparison between models and analyses of phylogenetic conservation throughout the models, the core mechanism(s) of these types of death. A main focus is on events in the less studied cell death types that are caspase-independent and non-apoptotic. These mechanisms will then be used to understand corresponding types of cell death in mammals, in particular humans. The general lines of inquiry followed in the WorkPackages (WP) include:
- analyzing distinct types of cell death in their respective optimal model(s)
- comparing cell death types within and between these models
- extending to corresponding cell death types in humans
Programmed cell death in plant, Podospora (top), Dictyostelium, Caenorhabditis (bottom).