Cross-Kingdom Analysis of Diversity, Evolutionary History, and Site Selection within the Eukaryotic Macrophage Migration Inhibitory Factor Superfamily

Abstract

Macrophage migration inhibitory factors (MIF) are multifunctional proteins regulating major processes in mammals, including activation of innate immune responses. MIF proteins also play a role in innate immunity of invertebrate organisms or serve as virulence factors in parasitic organisms, raising the question of their evolutionary history. We performed a broad survey of MIF presence or absence and evolutionary relationships across 803 species of plants, fungi, protists, and animals, and explored a potential relation with the taxonomic status, the ecology, and the lifestyle of individual species. We show that MIF evolutionary history in eukaryotes is complex, involving probable ancestral duplications, multiple gene losses and recent clade-specific re-duplications. Intriguingly, MIFs seem to be essential and highly conserved with many sites under purifying selection in some kingdoms (e.g., plants), while in other kingdoms they appear more dispensable (e.g., in fungi) or present in several diverged variants (e.g., insects, nematodes), suggesting potential neofunctionalizations within the protein superfamily.

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

“…Moreover, while plant MDLs were identified in data banks and their sequences and structures predicted by in silico methods (33,38), our current study offers the first experimental characterization of plant MDLs. In fact, little is known about plant MDLs.…”

“…Furthermore, MIF proteins are characterized by a unique enzymatic tautomerase activity at University of Groningen on January 13, 2020 http://www.jbc.org/ Downloaded from that is unprecedented in the chemokine-/cytokine group of proteins, and that is a notable component of the remarkable evolutionary conservation of the MIF sequence (8,25,61). MIF has been implicated as a player in various host-parasite interactions and MIF orthologs have been predicted to exist even in the plant kingdom (32,33,38).…”

“…MIF proteins exhibit a remarkable degree of evolutionary conservation across kingdoms, ranging from mammalians to vertebrates including fish, and unicellular parasites (8,25,32,33). Mammalian MIFs are intracellularly expressed and secreted from cytosolic pools via a non-conventional secretion pathway (13).…”

“…Based on sequence data bank information, the presence of MIF/D-DT-like proteins (MDLs) also is predicted in the plant kingdom, and we recently performed comprehensive in silico analyses of MDL genes/proteins across kingdoms and in the model plant Arabidopsis thaliana (AtMDLs) (33,38). The A. thaliana genome harbors three MDL genes and the predicted proteins exhibit a sequence identity of 28-33% to human MIF (HsMIF).…”

Separating cytokine twins with a small molecule

“…The MIF structure is evolutionarily conserved, and the MIF phylogenic tree can be traced back by several hundred million years. Interestingly, the structure of the MIF trimer resembles that of bacterial tautomerases, including conservation of the proline-containing catalytic pocket (5). Human and murine MIF exhibit catalytic tautomerase activity in vitro with 4-hydroxyphenylpyruvate and D-dopachrome identified as substrates, suggesting that MIF could have a dual role as a cytokine and enzyme.…”