Macrophage migration inhibitory factor

Macrophage migration inhibitory factor (MIF), also known as glycosylation-inhibiting factor (GIF), L-dopachrome isomerase, or phenylpyruvate tautomerase is a protein that in humans is encoded by the MIF gene.^[5][6] MIF is an important regulator of innate immunity.^[7] The MIF protein superfamily also includes a second member with functionally related properties, the D-dopachrome tautomerase (D-DT).^[8] CD74 is a surface receptor for MIF.^[9]

MIF
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1CA7, 1CGQ, 1GCZ, 1GD0, 1GIF, 1LJT, 1MIF, 1P1G, 2OOH, 2OOW, 2OOZ, 3B9S, 3CE4, 3DJH, 3DJI, 3HOF, 3IJG, 3IJJ, 3JSF, 3JSG, 3JTU, 3L5P, 3L5R, 3L5S, 3L5T, 3L5U, 3L5V, 3SMB, 3SMC, 3U18, 4ETG, 4EUI, 4EVG, 4F2K, 4GRN, 4GRO, 4GRP, 4GRQ, 4GRR, 4GRU, 3WNR, 3WNS, 3WNT, 4K9G, 4OSF, 4OYQ, 4P01, 4P0H, 4WR8, 4WRB, 4PKZ, 4PLU, 4TRF, 4TRU, 4XX7, 4XX8, 5BS9, 5BSC, 5BSI, 5EIZ, 5HVV, 5CG4, 5J7Q, 5BSJ, 5HVT, 4PKK, 5B4O, 5HVS, 5J7P
Identifiers
Aliases	MIF, GIF, GLIF, Mmacrophage migration inhibitory factor (glycosylation-inhibiting factor), macrophage migration inhibitory factor
External IDs	OMIM: 153620 MGI: 96982 HomoloGene: 55655 GeneCards: MIF
EC number	5.3.3.12
Gene location (Human) Chr. Chromosome 22 (human)^[1] Band 22q11.23 Start 23,894,383 bp^[1] End 23,895,227 bp^[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)^[2] Band 10 38.59 cM|10 C1 Start 75,695,187 bp^[2] End 75,696,074 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in anterior pituitary right adrenal gland renal cortex left adrenal gland superior frontal gyrus Brodmann area 9 right uterine tube hypothalamus kidney hippocampus proper Top expressed in otic placode somite maxillary prominence abdominal wall primitive streak hand endocardial cushion yolk sac internal carotid artery saccule More reference expression data BioGPS n/a
Gene ontology Molecular function cytokine activity isomerase activity protein binding chemoattractant activity phenylpyruvate tautomerase activity signaling receptor binding dopachrome isomerase activity protease binding cytokine receptor binding identical protein binding Cellular component vesicle myelin sheath nucleoplasm extracellular region cell surface extracellular exosome cytoplasm cytosol secretory granule lumen ficolin-1-rich granule lumen extracellular space Biological process positive regulation of protein phosphorylation negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator positive regulation of MAP kinase activity carboxylic acid metabolic process positive regulation of chemokine (C-X-C motif) ligand 2 production immune system process positive regulation of fibroblast proliferation DNA damage response, signal transduction by p53 class mediator negative regulation of apoptotic process negative regulation of mature B cell apoptotic process negative regulation of gene expression positive regulation of peptidyl-serine phosphorylation protein homotrimerization positive regulation of lipopolysaccharide-mediated signaling pathway cell surface receptor signaling pathway negative regulation of DNA damage response, signal transduction by p53 class mediator regulation of cell population proliferation positive regulation of arachidonic acid secretion positive regulation of B cell proliferation positive regulation of peptidyl-tyrosine phosphorylation positive regulation of prostaglandin secretion involved in immune response prostaglandin biosynthetic process innate immune response negative regulation of myeloid cell apoptotic process inflammatory response cell population proliferation positive regulation of phosphorylation positive regulation of myeloid leukocyte cytokine production involved in immune response leukocyte migration regulation of macrophage activation positive regulation of protein kinase A signaling positive chemotaxis neutrophil degranulation interleukin-12-mediated signaling pathway negative regulation of macrophage chemotaxis positive regulation of tumor necrosis factor production positive regulation of ERK1 and ERK2 cascade regulation of signaling receptor activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4282 17319 Ensembl ENSG00000276701 ENSG00000240972 ENSMUSG00000033307 UniProt P14174 P34884 RefSeq (mRNA) NM_002415 NM_010798 RefSeq (protein) NP_002406 NP_002406.1 NP_034928 Location (UCSC) Chr 22: 23.89 – 23.9 Mb Chr 10: 75.7 – 75.7 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Macrophage migration inhibitory factor (MIF)
Identifiers
Symbol	MIF
Pfam	PF01187
InterPro	IPR001398
PROSITE	PDOC00892
SCOP2	1mif / SCOPe / SUPFAM
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Bacterial antigens stimulate white blood cells to release MIF into the blood stream.^[10] The circulating MIF binds to CD74 on other immune cells to trigger an acute immune response. Hence, MIF is classified as an inflammatory cytokine. Furthermore, glucocorticoids also stimulate white blood cells to release MIF and hence MIF partially counteracts the inhibitory effects that glucocorticoids have on the immune system. Finally trauma activates the anterior pituitary gland to release MIF.^[11]

Structure

Macrophage migration inhibitory factor assembles into a trimer composed of three identical subunits. Each of these monomers contain two antiparallel alpha helices and a four-stranded beta sheet. The monomers surround a central channel with 3-fold rotational symmetry.^[12][13]

Response to injury

Cytokines play an important role in promoting wound healing and tissue repair. Cell injury results in MIF release which then interacts with CD74. MIF-CD74 signaling activates pro-survival and proliferative pathways that protects the host during injury.^[14]

Enzymatic activity

MIF contains two motifs with catalytic activity. The first is a 27 amino acid motif located at the N-terminus functions as a phenylpyruvate tautomerase that can catalyze the conversion of 2-carboxy-2,3-dihydroindole-5,6-quinone (dopachrome) into 5,6-dihydroxyindole-2-carboxylic acid (DHICA).^[15][16] MIF also contains a Cys-Ala-Leu-Cys catalytic site between residues 57 and 60 that appears to function as a disulfide reductase.^[17]

Function

This gene encodes a lymphokine involved in cell-mediated immunity, immunoregulation, and inflammation.^[18][19][20] MIF plays a role in the regulation of macrophage function in host defense through the suppression of anti-inflammatory effects of glucocorticoids.^[20][21][22] This lymphokine and the JAB1 protein form a complex in the cytosol near the peripheral plasma membrane, which may indicate a role in integrin signaling pathways.^[23]

Mechanism of action

MIF binds to CD74,^[24] inducing its phosphorylation and the recruitment of CD44 which then activates non-receptor tyrosine kinases, leading ultimately to extracellular signal-regulated kinase phosphorylation.^[25] In addition to ERK, stimulation of CD74 activates other signaling pathways such PI3K-Akt, NF-κB, and AMP-activated protein kinase (AMPK) pathways.^[26]

Interactions

Macrophage migration inhibitory factor has been reported to interact with:

• BNIPL,^[27]
• CD74,^{[28][29][30][31][32][33]}
• COPS5,^[34][35]
• CXCR4,^[36][37][38] and
• RPS19.^[39]

Clinical significance

MIF is a potential drug target for sepsis, rheumatoid arthritis, and cancer.^[40][41]

Parasite-produced MIF homologs

 

Parasite-Produced MIF Cytokine in Immune Evasion, Invasion, and Pathogenesis

Multiple protozoan parasites produce homologs MIF that have similar inflammatory functions to human MIF, and play a role in their pathogenesis, invasion and immune evasion.^[42][43] A preclinical study showed that blocking parasite MIF improves outcome in severe protozoan infections.^[44] Examples of protozoans with MIF homologs that have been reported:

• Entamoeba histolytica,^[45]
• Plasmodium falciparum,^[46]
• Toxoplasma gondii,^[47]
• Leishmania,^[48]
• Trichomonas vaginalis.^[49]

References

1. ENSG00000240972 GRCh38: Ensembl release 89: ENSG00000276701, ENSG00000240972 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000033307 – Ensembl, May 2017
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4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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