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Analyse évolutive et fonctionnelle des Macrophage Migration Inhibitory Factors chez les eucaryotes

Abstract : Macrophage migration inhibitory factors (MIF) are multifunctional proteins regulating major processes in mammals, including control of the cell cycle and migration, activation of innate immune responses, and prevention of p53-mediated apoptosis. MIF proteins also play a role in innate immunity of invertebrate organisms or serve as virulence factors in parasitic organisms, raising the question of their evolutionary history and of a putative differential evolution of structure/function relationships. The general aim of this PhD was to explore the diversity and evolutionary history of MIF proteins accross kingdoms, and to investigate their potential functional differences, with a special emphasis on host-parasite systems. We first performed a broad survey of MIF presence or absence and evolutionary relationships across 803 species of plants, fungi, protists, and animals, and explored a potential relation with the taxonomic status, the ecology, and the lifestyle of individual species. We show that MIF evolutionary history in eukaryotes is complex, involving ancestral duplications, multiple gene losses and recent clade-specific re-duplications. Of note, plants and plant parasites (other than fungi) harbour a median number of three MIFs, while heterotrophic and animal parasite species harbour a lower or/and variable MIF number. Intriguingly, MIFs seem to be essential and highly conserved with many sites under purifying selection in some kingdoms (e.g. plants), while in other kingdoms they appear more dispensable (e.g. in fungi) or present in several diverged variants (e.g. insects, nematodes), suggesting potential neofunctionalizations within the protein superfamily. We then analysed the effect of MIF proteins from selected species on plant cell death. All organisms tested (plant, oomycetes, protozoa, insects, and nematodes) including species that are not in interaction with plants, possess at least one MIF protein showing a significant cell death inhibitory effect. This suggests that plant cell death inhibition does not result from a neofunctionalization of MIF from plant-parasites, and is related to conserved structural features of MIF proteins. However, none of the parameters predicted in silico (sequence motifs, 3D structures, oligomerization, post-traductional modifications) appeared to be related to the cell death inhibitory activity. Future extensive functional studies are necessary to unravel the structure-function relationship of these evolutionarily and functionally complex proteins.
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Claire Michelet. Analyse évolutive et fonctionnelle des Macrophage Migration Inhibitory Factors chez les eucaryotes. Biologie moléculaire. Université Côte d'Azur, 2018. Français. ⟨NNT : 2018AZUR4109⟩. ⟨tel-02426269⟩

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