Macrophage migration inhibitory factor (MIF), also known as glycosylation-inhibiting factor (GIF), L-dopachrome isomerase, or phenylpyruvate tautomerase is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''MIF''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. MIF is an important regulator of

innate immunity The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...

. The MIF protein superfamily also includes a second member with functionally related properties, the D-dopachrome tautomerase (D-DT).

CD74 HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74 (Cluster of Differentiation 74), is a protein that in humans is encoded by the ''CD74'' gene. The invariant chain (Abbreviated Ii ...

is a surface receptor for MIF. Bacterial

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

s stimulate

white blood cell White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...

s to release MIF into the blood stream. The circulating MIF binds to

on other immune cells to trigger an acute immune response. Hence, MIF is classified as an

inflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include in ...

. Furthermore,

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...

s 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 Trauma most often refers to: * Major trauma, in physical medicine, severe physical injury caused by an external source * Psychological trauma, a type of damage to the psyche that occurs as a result of a severely distressing event *Traumatic i ...

activates the

anterior pituitary gland A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pi ...

to release MIF.

Structure

Macrophage migration inhibitory factor assembles into a trimer composed of three identical subunits. Each of these monomers contain two antiparallel

alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

and a four-stranded

beta sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a g ...

. The monomers surround a central channel with 3-fold

rotational symmetry Rotational symmetry, also known as radial symmetry in geometry, is the property a shape has when it looks the same after some rotation by a partial turn. An object's degree of rotational symmetry is the number of distinct orientations in which i ...

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

. MIF-CD74 signaling activates pro-survival and proliferative pathways that protects the host during injury.

Enzymatic activity

MIF contains two motifs with catalytic activity. The first is a 27 amino acid motif located at the

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

functions as a phenylpyruvate tautomerase that can catalyze the conversion of 2-carboxy-2,3-dihydroindole-5,6-quinone (

dopachrome Dopachrome is a cyclization product of L-DOPA and is an intermediate in the biosynthesis of melanin. It may tautomerise to form DHICA. See also * Dopachrome tautomerase Dopachrome tautomerase (dopachrome delta-isomerase, tyrosine-related pr ...

) into 5,6-dihydroxyindole-2-carboxylic acid (

DHICA DHICA (5,6-dihydroxyindole-2-carboxylic acid) is an intermediate in the biosynthesis of melanin. It may tautomerise to form Dopachrome Dopachrome is a cyclization product of L-DOPA and is an intermediate in the biosynthesis of melanin. It may t ...

). MIF also contains a Cys-Ala-Leu-Cys catalytic site between residues 57 and 60 that appears to function as a

disulfide In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

reductase A reductase is an enzyme that catalyzes a reduction reaction. Examples * 5α-Reductase * 5β-Reductase * Dihydrofolate reductase * HMG-CoA reductase * Methemoglobin reductase * Ribonucleotide reductase * Thioredoxin reductase * ''E. coli'' ...

Function

This gene encodes a

lymphokine Lymphokines are a subset of cytokines that are produced by a type of immune cell known as a lymphocyte. They are protein mediators typically produced by T cells to direct the immune system response by signaling between its cells. Lymphokines have m ...

involved in

cell-mediated immunity Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in ...

, immunoregulation, and

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

. MIF plays a role in the regulation of

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

function in host defense through the suppression of anti-inflammatory effects of

s. This lymphokine and the JAB1 protein form a complex in the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

near the peripheral plasma membrane, which may indicate a role in

integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

signaling pathways.

Mechanism of action

MIF binds to

, inducing its

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

and the recruitment of

CD44 The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhesi ...

which then activates

non-receptor tyrosine kinase A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases a ...

s, leading ultimately to

extracellular signal-regulated kinase In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and p ...

phosphorylation. In addition to ERK, stimulation of CD74 activates other signaling pathways such PI3K-Akt, NF-κB, and AMP-activated protein kinase (AMPK) pathways.

Interactions

Macrophage migration inhibitory factor has been reported to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: *

BNIPL Bcl-2/adenovirus E1B 19 kDa-interacting protein 2-like protein is a protein that in humans is encoded by the ''BNIPL'' gene. Interactions BNIPL has been shown to interact with: * BCL2-like 1, * Bcl-2 Bcl-2 (B-cell lymphoma 2), encoded in ...

, *

, * COPS5, *

CXCR4 C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor. Function CXCR-4 is an alpha-chemokin ...

, and *

RPS19 40S ribosomal protein S19 is a protein that in humans is encoded by the ''RPS19'' gene. Function Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are c ...

Clinical significance

MIF is a potential

drug target A biological target is anything within a living organism to which some other entity (like an endogenous ligand (biochemistry), ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes ...

for sepsis, rheumatoid arthritis, and cancer.

Parasite-produced MIF homologs

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. A preclinical study showed that blocking parasite MIF improves outcome in severe protozoan infections. Examples of protozoans with MIF homologs that have been reported: *

Entamoeba histolytica ''Entamoeba histolytica'' is an anaerobic parasitic amoebozoan, part of the genus ''Entamoeba''. Predominantly infecting humans and other primates causing amoebiasis, ''E. histolytica'' is estimated to infect about 35-50 million people worldwid ...

, *

Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...

, *

Toxoplasma gondii ''Toxoplasma gondii'' () is an obligate intracellular parasitic protozoan (specifically an apicomplexan) that causes toxoplasmosis. Found worldwide, ''T. gondii'' is capable of infecting virtually all warm-blooded animals, but felids, such as d ...

, *

Leishmania ''Leishmania'' is a parasitic protozoan, a single-celled organism of the genus '' Leishmania'' that are responsible for the disease leishmaniasis. They are spread by sandflies of the genus ''Phlebotomus'' in the Old World, and of the genus '' ...

, *

Trichomonas vaginalis ''Trichomonas vaginalis'' is an anaerobic, flagellated protozoan parasite and the causative agent of a sexually transmitted disease called trichomoniasis. It is the most common pathogenic protozoan that infects humans in industrialized countries ...

References

External links

* {{DEFAULTSORT:Macrophage Migration Inhibitory Factor Immune system