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Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs
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| Zeitschriftentitel: | Journal of Biological Chemistry |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , |
| In: | Journal of Biological Chemistry, 295, 2020, 3, S. 850-867 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Elsevier BV
|
| Schlagwörter: |
| author_facet |
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 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 |
|---|---|
| author |
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 |
| spellingShingle |
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 Journal of Biological Chemistry Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs Cell Biology Molecular Biology Biochemistry |
| author_sort |
sinitski, dzmitry |
| spelling |
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 0021-9258 1083-351X Elsevier BV Cell Biology Molecular Biology Biochemistry http://dx.doi.org/10.1074/jbc.ra119.009716 <jats:p>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/<jats:sc>d</jats:sc>-dopachrome tautomerase–like proteins or MDLs) of the model plant<jats:italic>Arabidopsis thaliana</jats:italic>. Recombinant<jats:italic>Arabidopsis</jats:italic>MDLs (<jats:italic>At</jats:italic>MDLs) share similar secondary structure characteristics with human MIF, yet only have minimal residual tautomerase activity using either<jats:italic>p</jats:italic>-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,<jats:italic>At</jats:italic>MDLs 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.</jats:p> Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs Journal of Biological Chemistry |
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10.1074/jbc.ra119.009716 |
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Elsevier BV, 2020 |
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Elsevier BV, 2020 |
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| title |
Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_unstemmed |
Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_full |
Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_fullStr |
Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_full_unstemmed |
Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_short |
Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_sort |
cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| topic |
Cell Biology Molecular Biology Biochemistry |
| url |
http://dx.doi.org/10.1074/jbc.ra119.009716 |
| publishDate |
2020 |
| physical |
850-867 |
| description |
<jats:p>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/<jats:sc>d</jats:sc>-dopachrome tautomerase–like proteins or MDLs) of the model plant<jats:italic>Arabidopsis thaliana</jats:italic>. Recombinant<jats:italic>Arabidopsis</jats:italic>MDLs (<jats:italic>At</jats:italic>MDLs) share similar secondary structure characteristics with human MIF, yet only have minimal residual tautomerase activity using either<jats:italic>p</jats:italic>-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,<jats:italic>At</jats:italic>MDLs 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.</jats:p> |
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| author | 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 |
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| description | <jats:p>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/<jats:sc>d</jats:sc>-dopachrome tautomerase–like proteins or MDLs) of the model plant<jats:italic>Arabidopsis thaliana</jats:italic>. Recombinant<jats:italic>Arabidopsis</jats:italic>MDLs (<jats:italic>At</jats:italic>MDLs) share similar secondary structure characteristics with human MIF, yet only have minimal residual tautomerase activity using either<jats:italic>p</jats:italic>-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,<jats:italic>At</jats:italic>MDLs 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.</jats:p> |
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| spelling | 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 0021-9258 1083-351X Elsevier BV Cell Biology Molecular Biology Biochemistry http://dx.doi.org/10.1074/jbc.ra119.009716 <jats:p>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/<jats:sc>d</jats:sc>-dopachrome tautomerase–like proteins or MDLs) of the model plant<jats:italic>Arabidopsis thaliana</jats:italic>. Recombinant<jats:italic>Arabidopsis</jats:italic>MDLs (<jats:italic>At</jats:italic>MDLs) share similar secondary structure characteristics with human MIF, yet only have minimal residual tautomerase activity using either<jats:italic>p</jats:italic>-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,<jats:italic>At</jats:italic>MDLs 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.</jats:p> Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs Journal of Biological Chemistry |
| spellingShingle | 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, Journal of Biological Chemistry, Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs, Cell Biology, Molecular Biology, Biochemistry |
| title | Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_full | Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_fullStr | Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_full_unstemmed | Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_short | Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_sort | cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| title_unstemmed | Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs |
| topic | Cell Biology, Molecular Biology, Biochemistry |
| url | http://dx.doi.org/10.1074/jbc.ra119.009716 |