The non-mammalian MIF superfamily

Abstract

Macrophage migration inhibitory factor (MIF) was first described as a cytokine 50 years ago, and emerged in mammals as a pleiotropic protein with pro-inflammatory, chemotactic, and growth-promoting activities. In addition, MIF has gained substantial attention as a pivotal upstream mediator of innate and adaptive immune responses and with pathologic roles in several diseases. Of less importance in mammals is an intrinsic but non-physiologic enzymatic activity that points to MIF's evolution from an ancient defense molecule. Therefore, it is not surprising that mif-like genes also have been found across a range of different organisms including bacteria, plants, protozoa, helminths, molluscs, arthropods, fish, amphibians and birds. While Genebank analysis identifying mif-like genes across species is extensive, contained herein is an overview of the non-mammalian MIF-like proteins that have been most well studied experimentally. For many of these organisms, MIF contributes to an innate defense system or plays a role in development. For parasitic organisms however, MIF appears to function as a virulence factor aiding in the establishment or persistence of infection by modulating the host immune response. Consequently, a combined targeting of both parasitic and host MIF could lead to more effective treatment strategies for parasitic diseases of socioeconomic importance.

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

“…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).…”

“…On the one hand, this appears unlikely, as plants do not express a major histocompatibility (MHC) system. However, CD74 has been found to be an amenable target of parasite MIF orthologs such as leishmania, plasmodium, or hookworm (32,35,37,71,72), suggesting that it is a receptor molecule prone to be engaged during host-parasite interactions. In fact, it has been suggested that the MIF binding functionality of CD74, which is best known as the MHC class II chaperone invariant chain Ii, already represents a "secondary" function of this membrane protein (16,73).…”

“…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).…”

“…Thus, it is not surprising that interactions between MIF/receptor networks from different species/kingdoms have been reported. However, these are so far confined to interactions between a mammalian host and parasitic microbes, with MIF proteins from pathogenic species employing molecular mimicry strategies to contribute to virulence and immune evasion mechanisms (32). For example, Plasmodium falciparum produces a MIF ortholog that modulates the host immune response to malaria by suppressing T-cell memory (35).…”

Role of Host and Parasite MIF Cytokines during Leishmania Infection

“…The discovery of Leishmania-encoded MIF orthologs is not entirely surprising, as MIF orthologs are found in organisms at all positions of the evolutionary tree, including protozoa, nematodes, plants, and invertebrate and vertebrate mammals alike. Furthermore, MIF orthologs have been reported in dozens of species of protozoan and helminthic parasites, and their properties have been thoroughly explored [100][101][102].…”