Protein-coding gene in the species Homo sapiens
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 factorExternal IDs
OMIM :
153620 ;
MGI :
96982 ;
HomoloGene :
55655 ;
GeneCards :
MIF ;
OMA :
MIF - orthologs
EC number
5.3.3.12
Wikidata
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:
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:
References
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b
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20485865 .
^
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b Takahashi K, Koga K, Linge HM, Zhang Y, Lin X, Metz CN, et al. (May 2009).
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2011PNAS..108.8224A .
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3100930 .
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^
"Entrez Gene: MIF macrophage migration inhibitory factor (glycosylation-inhibiting factor)" .
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Bibcode :
1993Natur.365..756B .
doi :
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PMID
8413654 .
S2CID
4321353 .
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7325688 .
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Bibcode :
2014PNAS..111.8179T .
doi :
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PMC
4050605 .
PMID
24843155 .
External links
PDB gallery
1ca7 : MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) WITH HYDROXPHENYLPYRUVATE
1cgq : MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) WITH ALANINE INSERTED BETWEEN PRO-1 AND MET-2
1gcz : MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) COMPLEXED WITH INHIBITOR.
1gd0 : HUMAN MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF)
1gif : HUMAN GLYCOSYLATION-INHIBITING FACTOR
1ljt : Crystal Structure of Macrophage Migration Inhibitory Factor complexed with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole-acetic acid methyl ester (ISO-1)
1mif : MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF)
1p1g : MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) WITH PRO-1 MUTATED TO GLY-1
2ooh : Crystal Structure of MIF bound to a Novel Inhibitor, OXIM-11
2oow : MIF Bound to a Fluorinated OXIM Derivative
2ooz : Macrophage Migration Inhibitory Factor (MIF) Complexed with OXIM6 (an OXIM Derivative Not Containing a Ring in its R-group)