Post-translational regulation of macrophage migration inhibitory factor: Basis for functional fine-tuning

Abstract

Macrophage migration inhibitory factor (MIF) is a chemokine-like protein and an important mediator in the inflammatory response. Unlike most other pro-inflammatory cytokines, a number of cell types constitutively express MIF and secretion occurs from preformed stores. MIF is an evolutionarily conserved protein that shows a remarkable functional diversity, including specific binding to surface CD74 and chemokine receptors and the presence of two intrinsic tautomerase and oxidoreductase activities. Several studies have shown that MIF is subject to post-translational modification, particularly redox-dependent modification of the catalytic proline and cysteine residues. In this review, we summarize and discuss MIF post-translational modifications and their effects on the biological properties of this protein. We propose that the redox-sensitive residues in MIF will be modified at sites of inflammation and that this will add further depth to the functional diversity of this intriguing cytokine.

Keywords: Carbamylation; Cytokine; Inflammation; Myeloperoxidase; N-terminal proline; OxMIF; Post-translational modification; Redox regulation; Tautomerase.

Fig. 1

A) Amino acid sequence of MIF with residues targeted for post-translational modifications highlighted in colour. Note: the suggested cysteine-oxidized form is speculative and lacks structural confirmation. B) Ribbon structure of the MIF trimer based in the PDB crystal structure 3DJH (1.25 Å resolution) with the side chain susceptible to post-translational modifications shown in coloured spheres: red – Pro-2, blue – Cys-57/Cys-60, green – Cys-81, purple – Ser-91, orange yellow – Ser-112/Thr-113. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Post-translational modifications of MIF inside and outside the cell. Posttranslational removal of the N-terminal methionine in MIF results in an N-terminal proline (Pro-2) in the mature protein. The N-terminal proline can be modified by neutrophil-derived oxidants, carbamylation and binding of electrophiles such as isothiocyanate (ITC). MIF can be cysteinylated at Cys-60 and a conformational change can occur at the ß-sheet encompassing Cys-57/60. S-nitrosation and phosphorylation can modify Cys-81and Ser-91, respectively.