Structural and functional basis of the regulatory role of MDL proteins in plant and human immunity

• Applicants: Professor Dr. Jürgen Bernhagen; Professor Dr. Ralph Panstruga
• Subject Area: Organismic Interactions, Chemical Ecology and Microbiomes of Plant Systems ; Biochemistry ; Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544968819

The chemokine-like cytokine macrophage migration inhibitory factor (MIF) is a prominent disease marker and pivotal mediator of human inflammatory and immune diseases. Despite progress in the discovery of MIF receptor pathways, translational applications and a comprehensive mechanistic understanding of MIF’s pathobiology are incomplete. Strikingly, MIF is a highly conserved protein found across all kingdoms of life, including plants. The elucidation of the structural and functional properties of MIF proteins from plants could help to understand disease mechanisms of human MIF. However, MIF orthologs in plants remain poorly studied. In the context of our previous project X-KINGDOM-MIF, we have begun to characterize immune-related functions of MIF/D-DT-like proteins (MDLs) from the model plant A. thaliana and to study cross-kingdom structure-function specificities between human MIF and MDLs. In addition to an initial in planta analysis of MDL proteins in Arabidopsis including the identification of potential MDL interactors, key findings were the elucidation of the 3D structure of all three MDL proteins and the identification of synergistic interactions of human MIF and plant MDLs on human receptor activation. Capitalizing on these findings, the overarching goal of our proposal will be to scrutinize the mechanisms of how MDLs modulate immunity, both in a cross-kingdom manner at the interface with the human/mammalian immune system and in plants themselves. We will deepen the mechanistic understanding of the MIF-MDL interplay in the context of mammalian immunity, elucidate the mechanism and structural determinants of MIF/MDL synergism on the MIF receptors CXCR2 and CXCR4, and define the role of synergism in vivo. On the other hand, we aim to explore the role of MDL proteins in plant immunity. Another objective will be to identify the natural enzymatic substrate(s) of the tautomerase cavity both for human MIF and plant MDLs using untargeted snapshot metabolomics. Lastly, our prior results from the model plant Arabidopsis will be expanded to MDLs from eatable plants such as tomato to test the hypothesis that food-based MDLs may interact with MIF to modulate human immunity. All aims will benefit from the expertise and tools of both applicants, synergistically complementing plant and human biology expertise. In summary, our proposal will address key questions regarding the human-plant MIF cross-kingdom relationship and define their synergistic activities on molecular level, while testing its relevance in physiology and disease.

• DFG Programme: Research Grants