Macrophage migration inhibitory factor

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)
External IDs	OMIM: 153620 MGI: 96982 HomoloGene: 55655 GeneCards: MIF
EC number	5.3.3.12
Gene ontology Molecular function • cytokine activity • isomerase activity • protein binding • chemoattractant activity • phenylpyruvate tautomerase activity • receptor binding • dopachrome isomerase activity • cytokine receptor binding Cellular component • cytoplasm • vesicle • myelin sheath • nucleoplasm • extracellular fluid • extracellular region • cell surface • extracellular exosome Biological process • positive regulation of protein phosphorylation • negative regulation of cellular protein metabolic process • 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 • negative regulation of cell aging • positive regulation of cytokine secretion • 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 • negative regulation of cell cycle arrest • positive regulation of lipopolysaccharide-mediated signaling pathway • cell aging • cell surface receptor signaling pathway • negative regulation of DNA damage response, signal transduction by p53 class mediator • regulation of cell proliferation • positive regulation of arachidonic acid secretion • positive regulation of B cell proliferation • positive regulation of ERK1 and ERK2 cascade • 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 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 Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4282	17319
Ensembl	n/a	ENSMUSG00000033307
UniProt	P14174	P34884
RefSeq (mRNA)	NM_002415	NM_010798
RefSeq (protein)	NP_002406.1 NP_002406.1	NP_034928.1
Location (UCSC)	Chr 22: 23.89 – 23.9 Mb	Chr 10: 75.86 – 75.86 Mb
PubMed search	[1]	[2]
Wikidata

Macrophage migration inhibitory factor (MIF or MMIF), 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.^[3][4] MIF is an important regulator of innate immunity.^[5]

Bacterial antigens stimulate white blood cells to release MIF into the blood stream.^[6] 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.^[7]

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.^[8][9]

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).^[10][11] MIF also contains a Cys-Ala-Leu-Cys catalytic site between residues 57 and 60 that appears to function as a disulfide reductase.^[12]

Function

This gene encodes a lymphokine involved in cell-mediated immunity, immunoregulation, and inflammation.^[13][14][15] MIF plays a role in the regulation of macrophage function in host defense through the suppression of anti-inflammatory effects of glucocorticoids.^[15][16][17] 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.^[18]

Mechanism of action

MIF binds to CD74,^[19] inducing its phosphorylation and the recruitment of CD44 which then activates non-receptor tyrosine kinases, leading ultimately to extracellular signal-regulated kinase phosphorylation.^[20]

Interactions

Macrophage migration inhibitory factor has been reported to interact with:

• BNIPL,^[21]
• CD74,^{[22][23][24][25][26]}
• COPS5,^[27]
• CXCR4,^[28][29][30] and
• RPS19.^[31]

Clinical significance

MIF is an inflammatory mediator associated with rheumatoid arthritis (RA) severity.^[32][33][34] MIF protein levels are increased in the plasma of people with schizophrenia, including people in the early stages of the illness, but the clinical significance of this has not been determined.^[35][36]

It has also been shown to induce changes in the heart during sepsis.^[37]

Evidence suggests that there is a correlation between MIF production and metastatic potential in colorectal cancer.^[38]

In addition, it was reported that there is an increased MIF production in Alzheimer's disease and mild cognitive impairment.^[39]

References