X-KINGDOM-MIF - Cross-kingdom analysis of macrophage migration inhibitory factor (MIF) functions

• Applicants: Professor Dr. Jürgen Bernhagen; Professor Dr. Karl-Heinz Kogel; Professor Dr. Ralph Panstruga
• Subject Area: Organismic Interactions, Chemical Ecology and Microbiomes of Plant Systems ; Evolutionary Cell and Developmental Biology (Zoology) ; Immunology ; Plant Physiology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 316495857

• Final Report Year: 2022

Final Report Abstract

In this project, we used a cross-kingdom comparative approach to study the activities of multifunctional MIF proteins in members of different kingdoms of life (mammals, plants, aphids, fungi and protists). In humans, MIF (macrophage migration inhibitory factor) is a key signaling molecule implicated in immunity, and, therefore, its function decisively determines the outcome of infectious and inflammatory diseases and other adverse conditions. In a comprehensive in silico analysis, we first explored the diversity and deduced the evolutionary history of MIF proteins across organisms from all kingdoms of life. Our experimental approaches revealed that, unexpectedly, plant MIF proteins (MDLs) can bind to human MIF receptors and trigger signaling events in human cells. Yet unpublished work also successfully elucidated the structures of all three MDLs of the model plant Arabidopsis thaliana and identified an oligomerization-based mechanism of human/plant MIF synergism. We further showed that MDL functions in plants are related to controlling flowering time and modulating antibacterial immunity. We finally explored the potential of MIF genes as targets for insect control. In sum, our work expanded significantly the knowledge about a highly conserved eukaryotic protein family, which apart from mammals have not been studied extensively in other organismal taxa.

Publications

• Cross-kingdom analysis of diversity, evolutionary history, and site selection within the eukaryotic macrophage migration inhibitory factor superfamily. Genes 2019; 10: E740
  Michelet C, Danchin EGJ, Jaouannet M, Bernhagen J, Panstruga R, Kogel K-H, Keller H, Coustau C
  
• Atypical membrane-anchored cytokine MIF in a marine dinoflagellate. Microorganisms. 2020; 8:1263
  Jaouannet M, Pavaux AS, Pagnotta S, Pierre O, Michelet C, Marro S, Keller H, Lemée R, Coustau C
  
• Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs. J Biol Chem 2020; 295:850–67
  Sinitski D, Gruner K, Brandhofer M, Kontos C, Winkler P, Reinstädler A, Bourilhon P, Xiao Z, Cool R, Kapurniotu A, Dekker FJ, Panstruga R, Bernhagen J
  
• RNA-based technologies for insect control in plant production. Biotechnol Adv 2020; 39:107463
  Liu S., Jaouannet M., Dempsey DMA, Imani J., Coustau C, Kogel K-H
  
• Studying plant MIF/D-DT-like genes and proteins (MDLs). Methods Mol Biol 2020; 2080:249–61
  Sinitski D, Gruner K, Bernhagen J, Panstruga R
  
• Chemokine-like MDL proteins modulate flowering time and innate immunity in plants. J Biol Chem 2021; 296: 100611
  Gruner K, Leissing F, Sinitski D, Thieron H, Axstmann C, Baumgarten K, Reinstädler A, Winkler P, Altmann M, Flatley A, Jaouannet M, Zienkiewicz K, Feussner I, Keller H, Coustau C, Falter-Braun P, Feederle R, Bernhagen J, Panstruga R
  
• Evaluation of dsRNA delivery methods for targeting macrophage migration inhibitory factor (MIF) in RNAi-based aphid control. J Plant Dis Prot 2021; 128: 1201–1212
  Liu S, Ladera-Carmona MJ, Poranen MM, van Bel Aart J.E., Kogel K-H, Imani J
  
• A cross-kingdom view on the immunomodulatory role of MIF/D-DT proteins in mammalian and plant Pseudomonas infections. Immunology
  Panstruga R, Donnelly SC, Bernhagen J