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Macrophage migration inhibitory factor

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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
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMIF, GIF, GLIF, Mmacrophage migration inhibitory factor (glycosylation-inhibiting factor), macrophage migration inhibitory factor
External IDsOMIM: 153620; MGI: 96982; HomoloGene: 55655; GeneCards: MIF; OMA:MIF - orthologs
EC number5.3.3.12
Orthologs
SpeciesHumanMouse
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 MbChr 10: 75.7 – 75.7 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Macrophage migration inhibitory factor (MIF)
Identifiers
SymbolMIF
PfamPF01187
InterProIPR001398
PROSITEPDOC00892
SCOP21mif / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure 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

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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

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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

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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

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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

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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

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Macrophage migration inhibitory factor has been reported to interact with:

Clinical significance

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

Parasite-produced MIF homologs

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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:

References

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  1. ^ a b c ENSG00000240972 GRCh38: Ensembl release 89: ENSG00000276701, ENSG00000240972 – Ensembl, May 2017
  2. ^ a b c 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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  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.
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  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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