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Macrophage migration inhibitory factor (MIF) and its homologue D-dopachrome tautomerase (D-DT) are ubiquitous, pro-inflammatory cytokines with chemokine-like functions that coordinate a wide spectrum of biological activities like migration. Here, we biotin-tagged intracellular MIF/D-DT in vivo to identify important cytosolic interactors and found a plethora of actin cytoskeleton-associated proteins. While the CD74/CD44 receptor complex is essential for signalling transduction in fibroblasts by extracellular MIF/D-DT, our interactome data rather suggested direct effects. We thus investigated whether MIF/D-DT can modulate cell migration independent of CD74/CD44. To differentiate between receptor- and non-receptor-mediated motility, we treated fibroblasts that are deficient in CD74 and CD44 or that express both proteins with recombinant MIF/D-DT. Interestingly, only MIF could stimulate chemokinesis in the presence or absence of CD74/CD44. The pro-migratory effects of MIF depended on lipid raft/caveolae-mediated but not clathrin-mediated endocytosis, on its tautomerase activity and, likely, on its thiol protein oxidoreductase activity. As MIF treatment restrained actin polymerisation in vitro our findings establish a new intracellular role for MIF/D-DT in driving cell motility by modulating the actin cytoskeleton.

Extracellular MIF, but not its homologue D-DT, promotes fibroblast motility independent of its receptor CD74/CD44