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), macrophage migration inhibitory factor
External IDs	OMIM: 153620; MGI: 96982; HomoloGene: 55655; GeneCards: MIF; OMA:MIF - orthologs
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 left adrenal cortex C1 segment right uterine tube right adrenal cortex Top expressed in embryo embryo otic placode otic vesicle somite maxillary prominence abdominal wall mandibular prominence epiblast migratory enteric neural crest cell 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
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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

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]

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
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Weiser WY, Temple PA, Witek-Giannotti JS, Remold HG, Clark SC, David JR (October 1989). "Molecular cloning of a cDNA encoding a human macrophage migration inhibitory factor". Proceedings of the National Academy of Sciences of the United States of America. 86 (19): 7522–6. Bibcode:1989PNAS...86.7522W. doi:10.1073/pnas.86.19.7522. PMC 298097. PMID 2552447.
6. Kozak CA, Adamson MC, Buckler CE, Segovia L, Paralkar V, Wistow G (June 1995). "Genomic cloning of mouse MIF (macrophage inhibitory factor) and genetic mapping of the human and mouse expressed gene and nine mouse pseudogenes". Genomics. 27 (3): 405–11. doi:10.1006/geno.1995.1070. PMID 7558020.
7. Calandra T, Roger T (October 2003). "Macrophage migration inhibitory factor: a regulator of innate immunity". Nature Reviews. Immunology. 3 (10): 791–800. doi:10.1038/nri1200. PMC 7097468. PMID 14502271.
8. Günther S, Fagone P, Jalce G, Atanasov AG, Guignabert C, Nicoletti F (February 2019). "Role of MIF and D-DT in immune-inflammatory, autoimmune, and chronic respiratory diseases: from pathogenic factors to therapeutic targets". Drug Discovery Today. 24 (2): 428–439. doi:10.1016/j.drudis.2018.11.003. PMID 30439447. S2CID 53562815.
9. Farr L, Ghosh S, Moonah S (2020). "Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair". Frontiers in Immunology. 11: 1273. doi:10.3389/fimmu.2020.01273. PMC 7325688. PMID 32655566.
10. Barret, James (1980). Basic Immunology and its Medical Application (2 ed.). St.Louis: The C.V. Mosby Company. ISBN 978-0-8016-0495-9.
11. Larson DF, Horak K (2006). "Macrophage migration inhibitory factor: controller of systemic inflammation". Critical Care. 10 (2): 138. doi:10.1186/cc4899. PMC 1550887. PMID 16677407.
12. Sun HW, Bernhagen J, Bucala R, Lolis E (May 1996). "Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor". Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5191–6. doi:10.1073/pnas.93.11.5191. PMC 39220. PMID 8643551.
13. Al-Abed Y, VanPatten S (January 2011). "MIF as a disease target: ISO-1 as a proof-of-concept therapeutic". Future Medicinal Chemistry. 3 (1): 45–63. doi:10.4155/fmc.10.281. PMID 21428825.
14. Farr L, Ghosh S, Moonah S (2020). "Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair". Frontiers in Immunology. 11: 1273. doi:10.3389/fimmu.2020.01273. PMC 7325688. PMID 32655566.
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22. Al-Abed Y, Metz CN, Cheng KF, Aljabari B, VanPatten S, Blau S, et al. (May 2011). "Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity". Proceedings of the National Academy of Sciences of the United States of America. 108 (20): 8224–7. Bibcode:2011PNAS..108.8224A. doi:10.1073/pnas.1017624108. PMC 3100930. PMID 21536912.
23. "Entrez Gene: MIF macrophage migration inhibitory factor (glycosylation-inhibiting factor)".
24. Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, et al. (October 1993). "MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia". Nature. 365 (6448): 756–9. Bibcode:1993Natur.365..756B. doi:10.1038/365756a0. PMID 8413654. S2CID 4321353.
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26. Farr L, Ghosh S, Moonah S (2020). "Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair". Frontiers in Immunology. 11: 1273. doi:10.3389/fimmu.2020.01273. PMC 7325688. PMID 32655566.
27. Shen L, Hu J, Lu H, Wu M, Qin W, Wan D, et al. (April 2003). "The apoptosis-associated protein BNIPL interacts with two cell proliferation-related proteins, MIF and GFER". FEBS Letters. 540 (1–3): 86–90. doi:10.1016/S0014-5793(03)00229-1. PMID 12681488.
28. Farr L, Ghosh S, Jiang N, Watanabe K, Parlak M, Bucala R, Moonah S (2020). "CD74 Signaling Links Inflammation to Intestinal Epithelial Cell Regeneration and Promotes Mucosal Healing". Cellular and Molecular Gastroenterology and Hepatology. 10 (1): 101–112. doi:10.1016/j.jcmgh.2020.01.009. PMC 7215244. PMID 32004754.
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32. Wang F, Shen X, Guo X, Peng Y, Liu Y, Xu S, Yang J (February 2010). "Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats". Pain. 148 (2): 275–83. doi:10.1016/j.pain.2009.11.011. PMID 20005040. S2CID 38141283.
33. Dobson SE, Augustijn KD, Brannigan JA, Schnick C, Janse CJ, Dodson EJ, et al. (December 2009). "The crystal structures of macrophage migration inhibitory factor from Plasmodium falciparum and Plasmodium berghei". Protein Science. 18 (12): 2578–91. doi:10.1002/pro.263. PMC 2798171. PMID 19827093.
34. Ghosh S, Leaton LA, Farr L, Barfield A, Moonah S (July 2018). "Interaction between parasite-encoded JAB1/CSN5 and macrophage migration inhibitory factor proteins attenuates its proinflammatory function". Scientific Reports. 8 (1): 10241. Bibcode:2018NatSR...810241G. doi:10.1038/s41598-018-28625-1. PMC 6035221. PMID 29980718.
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38. Stosic-Grujicic S, Stojanovic I, Maksimovic-Ivanic D, Momcilovic M, Popadic D, Harhaji L, et al. (June 2008). "Macrophage migration inhibitory factor (MIF) is necessary for progression of autoimmune diabetes mellitus". Journal of Cellular Physiology. 215 (3): 665–75. doi:10.1002/jcp.21346. PMID 18064633. S2CID 36047003.
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45. Ngobeni R, Abhyankar MM, Jiang NM, Farr LA, Samie A, Haque R, Moonah SN (April 2017). "Entamoeba histolytica-Encoded Homolog of Macrophage Migration Inhibitory Factor Contributes to Mucosal Inflammation during Amebic Colitis". The Journal of Infectious Diseases. 215 (8): 1294–1302. doi:10.1093/infdis/jix076. PMC 5853319. PMID 28186296.
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47. Sommerville C, Richardson JM, Williams RA, Mottram JC, Roberts CW, Alexander J, Henriquez FL (May 2013). "Biochemical and immunological characterization of Toxoplasma gondii macrophage migration inhibitory factor". The Journal of Biological Chemistry. 288 (18): 12733–41. doi:10.1074/jbc.M112.419911. PMC 3642319. PMID 23443656.
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49. Twu O, Dessí D, Vu A, Mercer F, Stevens GC, de Miguel N, et al. (June 2014). "Trichomonas vaginalis homolog of macrophage migration inhibitory factor induces prostate cell growth, invasiveness, and inflammatory responses". Proceedings of the National Academy of Sciences of the United States of America. 111 (22): 8179–84. Bibcode:2014PNAS..111.8179T. doi:10.1073/pnas.1321884111. PMC 4050605. PMID 24843155.

External links

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