In:
Journal of Biological Chemistry, Elsevier BV, Vol. 295, No. 3 ( 2020-01-17), p. 850-867
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 -dopachrome tautomerase–like proteins or MDLs) of the model plant Arabidopsis thaliana . Recombinant Arabidopsis MDLs ( At MDLs) 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, At 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.
Type of Medium:
Online Resource
ISSN:
0021-9258
,
1083-351X
DOI:
10.1074/jbc.RA119.009716
Language:
English
Publisher:
Elsevier BV
Publication Date:
2020
detail.hit.zdb_id:
2141744-1
detail.hit.zdb_id:
1474604-9
SSG:
12
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