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

Sinitski, Dzmitry ; Gruner, Katrin ; Brandhofer, Markus ; Kontos, Christos ; Winkler, Pascal ; Reinstädler, Anja ; Bourilhon, Priscila ; Xiao, Zhangping ; Cool, Robbert ; Kapurniotu, Aphrodite ; Dekker, Frank J. ; Panstruga, Ralph ; Bernhagen, Jürgen

The Journal of biological chemistry, 2020-01, Vol.295 (3), p.850-867 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs
Autor: Sinitski, Dzmitry ; Gruner, Katrin ; Brandhofer, Markus ; Kontos, Christos ; Winkler, Pascal ; Reinstädler, Anja ; Bourilhon, Priscila ; Xiao, Zhangping ; Cool, Robbert ; Kapurniotu, Aphrodite ; Dekker, Frank J. ; Panstruga, Ralph ; Bernhagen, Jürgen
Assuntos: Antigens, Differentiation, B-Lymphocyte - chemistry ; Antigens, Differentiation, B-Lymphocyte - genetics ; Arabidopsis - genetics ; Arabidopsis - immunology ; CD74 ; cellular immune response ; chemokine ; Chemotaxis - genetics ; Chemotaxis - immunology ; Conserved Sequence - genetics ; Conserved Sequence - immunology ; CXC chemokine receptor type 4 (CXCR-4) ; cytokine ; Cytokines - genetics ; Cytokines - immunology ; HEK293 Cells ; Histocompatibility Antigens Class II - chemistry ; Histocompatibility Antigens Class II - genetics ; Humans ; Immunity, Innate - genetics ; inflammation ; innate immunity ; Intramolecular Oxidoreductases - chemistry ; Intramolecular Oxidoreductases - genetics ; Intramolecular Oxidoreductases - immunology ; Macrophage Migration-Inhibitory Factors - chemistry ; Macrophage Migration-Inhibitory Factors - genetics ; Macrophage Migration-Inhibitory Factors - immunology ; MIF ; migration ; Monocytes - chemistry ; Monocytes - metabolism ; plant defense ; Protein Binding - genetics ; protein conformation ; Receptors, CXCR4 - chemistry ; Receptors, CXCR4 - genetics ; Sequence Homology ; structure–function ; T-Lymphocytes - chemistry ; T-Lymphocytes - metabolism
É parte de: The Journal of biological chemistry, 2020-01, Vol.295 (3), p.850-867
Descrição: 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-dopachrome tautomerase–like proteins or MDLs) of the model plant Arabidopsis thaliana. Recombinant Arabidopsis MDLs (AtMDLs) share similar secondary structure characteristics 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 the 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 toward 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 its plant orthologs. This may point toward a previously unrecognized interplay between plant proteins and the human innate immune system.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

Sinitski, Dzmitry ; Gruner, Katrin ; Brandhofer, Markus ; Kontos, Christos ; Winkler, Pascal ; Reinstädler, Anja ; Bourilhon, Priscila ; Xiao, Zhangping ; Cool, Robbert ; Kapurniotu, Aphrodite ; Dekker, Frank J. ; Panstruga, Ralph ; Bernhagen, Jürgen

United States: Elsevier Inc

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