Editors' ChoiceBiochemistry

Plant chemokine mimics

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Science Signaling  28 Jan 2020:
Vol. 13, Issue 616, eabb0387
DOI: 10.1126/scisignal.abb0387

Human immune cells migrate in response to plant chemokine orthologs that bind to and activate the chemokine receptor CXCR4.

Human macrophage migration-inhibitory factor (MIF) is a cytokine that has tautomerase activity and chemokine-like properties. MIF binds to and stimulates various chemokine receptors, including CXCR4, to induce immune cell migration and regulate host immunity. The MIF-CXCR4 signaling axis is implicated in inflammation, atherosclerosis, and metastasis. Noting that MIF proteins are evolutionarily conserved and are thought to be ancient enzymes that gained extra regulatory functions through evolution, Sinitski et al. studied the family of three MDL proteins that are encoded by the plant Arabidopsis thaliana (AtMDLs) and have about 30% sequence homology with human MIF. The authors found that recombinant AtMDL proteins folded similarly to recombinant human MIF and that their secondary structures were similar as assessed by circular dichroism spectroscopy. In comparison to human MIF, the AtMDL proteins had minimal tautomerase activity in vitro, likely due to steric impedance of the substrate-binding pocket. However, AtMDLs bound to CXCR4 in yeast cell transformants and stimulated CXCR4 signaling in HEK293 cells to activate the PI3K-Akt pathway. In vitro, AtMDL1 was as efficient as human MIF in stimulating the migration of human monocytes through CXCR4. AtMDLs also acted as chemoattractants for primary human T cells in vitro in a CXCR4-dependent manner, and pretreatment of T cells with AtMDLs desensitized subsequent responses to human MIF and the CXCR4 ligand CXCL12. Together, these data suggest that plant proteins with homology to a human cytokine can bind to and stimulate signaling through human receptors, which has implications for how these plant proteins might modulate human immune responses.

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