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Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs.

J Biol Chem. 2019 Dec 6. pii: jbc.RA119.009716. doi: 10.1074/jbc.RA119.009716. [Epub ahead of print]

Authors/Editors: Sinitski D, Gruner K, Brandhofer M, Kontos C, Winkler P, Reinstädler A, Bourilhon P, Xiao Z, Cool RH, Kapurniotu A, Dekker FJ, Panstruga R, Bernhagen J.
Publication Date: 2019

Abstract

Human macrophage migration-inhibitory factor (MIF) is an evolutionarily conserved protein that has both extracellular immune-modulating and intracellular cell-regulatory functions. MIF plays a role in various diseases including inflammatory diseases, atherosclerosis, autoimmunity, and cancer. It serves as an inflamma­­tory cytokine and chemokine, but also exhibits enzymatic activity. Secreted MIF binds to cell-surface immune recep­tors such as CD74 and CXCR4. Plants possess MIF orthologs but lack the associated receptors, suggesting functional diversification across kingdoms. Here we characterized three MIF orthologs (termed MIF/D-DT-like proteins or MDLs) of the model plant Arabidopsis thaliana. Recombinant Arabidopsis MDLs (AtMDLs) share similar secondary structurecharacteristics with human MIF, yet only have minimal residual tautomerase activity using either p-hydroxyphenylpyruvate or dopachrome methyl ester as substrate. Site-specific mutagenesis suggests that this is due to a distinct amino acid difference at catalytic cavity-defining residue Asn-98. Surprisingly, AtMDLs bind to the human MIF receptors CD74 and CXCR4. Moreover, they activate CXCR4-dependent signaling in a receptor-specific yeast reporter system and in CXCR4-expressing human HEK293 trans­fectants. Notably, plant MDLs exert dose-dependent chemotactic activity towards human monocytes and T cells. A small molecule MIF inhibitor and an allosteric CXCR4 inhibitor counteract this function, revealing its specificity. Our results indicate cross-kingdom conservation of the receptor signaling and leukocyte recruitment capacities of human MIF by plant orthologs. This may point towards a previously unrecognized interplay between plant proteins and the human innate immune system.

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