D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family

Abstract

D-dopachrome tautomerase (D-DT) is a newly described cytokine and a member of the macrophage migration inhibitory factor (MIF) protein superfamily. MIF is a broadly expressed pro-inflammatory cytokine that regulates both the innate and the adaptive immune response. MIF activates the MAP kinase cascade, modulates cell migration, and counter-acts the immunosuppressive effects of glucocorticoids. For many cell types, MIF also acts as an important survival or anti-apoptotic factor. Circulating MIF levels are elevated in the serum in different infectious and autoimmune diseases, and neutralization of the MIF protein via antibodies or small molecule antagonists improves the outcome in numerous animal models of human disease. Recently, a detailed investigation of the biological role of the closely homologous protein D-DT, which is encoded by a gene adjacent to MIF, revealed an overlapping functional spectrum with MIF. The D-DT protein also is present in most tissues and circulates in serum at similar concentrations as MIF. D-DT binds the MIF cell surface receptor complex, CD74/CD44, with high affinity and induces similar cell signaling and effector functions. Furthermore, an analysis of the signaling properties of the two proteins showed that they work cooperatively, and that neutralization of D-DT in vivo significantly decreases inflammation. In this review, we highlight the similarities and differences between MIF and D-DT, which we propose to designate "MIF-2", and discuss the implication of D-DT/MIF-2 expression for MIF-based therapies.

Fig. 1. X-Ray Structure of Human D-DT and MIF

A) Three dimensional structure of D-DT. Left panel: Human D-DT monomer. Right: Human D-DT trimer. Structures are drawn from PDB entry 1DPT using PyMOL. B) Three dimensional structure of MIF. Left panel: Human MIF monomer. Right: Human MIF trimer. Structures are drawn from PDB entry 1MIF using PyMOL.

Fig. 2. Sequence alignment of selected D-DT or MIF proteins

A) Sequence alignment of selected D-DT proteins. The accession numbers are: H. sapiens CAG30317.1, M. mulatta XP_001087658.1, B. taurus NP_001092620.1, M. musculus NP_034157.1, G. gallus NP_001025838.1, D. rerio NP_001002147.1 B) Sequence alignment of selected MIF proteins. The accession numbers are: H. sapiens CAG30406.1, M. mulatta AAT74528.2, B. taurus DAA20377.1, M. musculus NP_034928.1, G. gallus AAA48939.1, D. rerio NP_001036786.1.