The interferon-gamma receptor (IFNGR)

protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain. Protein ...

is the heterodimer of two chains:

IFNGR1 Interferon gamma receptor 1 (IFNGR1) also known as CD119 (Cluster of Differentiation 119), is a protein that in humans is encoded by the ''IFNGR1'' gene. Function The gene ''IFNGR1'' encodes IFN-γR1, which is the ligand-binding chain (alpha) o ...

and IFNGR2. It binds

interferon-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

, the sole member of

interferon type II Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...

Structure and function

The human interferon-gamma receptor complex consists the heterodimer of two chains:

and IFNGR2. In unstimulated cells, these subunits are not preassociated with each other but rather associate through their intracellular domains with inactive forms of specific Janus family kinases (Jak1 and Jak2). Jak1 and Jak2 constitutively associate with IFNGR1 and IFNGR2, respectively. Binding of IFN-γ to IFNGR1 induces the rapid dimerization of IFNGR1 chains, thereby forming a site that is recognized by the extracellular domain of IFNGR2. The ligand-induced assembly of the complete receptor complex contains two IFNGR1 and two IFNGR2 subunits, which bring into close juxtaposition the intracellular domains of these proteins together with the inactive Jak1 and Jak2 kinases that they associate with. In this complex, Jak1 and Jak2 transactivate one another and then phosphorylate IFNGR1, thereby forming a paired set of

Stat1 Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family. Function All STAT molecules are phosphorylated by receptor associ ...

docking sites on the ligated receptor. Two Stat1 molecules then associate with the paired docking sites, are brought into close proximity with receptor-associated-activated JAK kinases, and are activated by phosphorylation of the Stat1. Tyrosine-phosphorylated Stat1 molecules dissociate from their receptor tether and form homodimeric complexes. Activated Stat1 translocates to the nucleus and, after binding to a specific sequence in the promoter region of immediate-early IFN-γ-inducible genes, effects gene

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

Disease linkage

IFNGR1 deficiency is associated with the increased susceptibility to certain infectious diseases in patients, especially mycobacterial infections.

Mutations

Disseminated BCG infections occur in infants with SCID or with other severe T cell defects. However, in approximately half of the cases no specific host defect has been found. One possible explanation for this predilection was found in a 2.5-month-old Tunisian female infant who had fatal

idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kin ...

disseminated BCG infection. In four children from Malta who had disseminated atypical mycobacterial infection in the absence of a recognized immunodeficiency. In the case of all five children, there was consanguinity in their pedigrees. All affected were found to have a functional defect in the upregulation of TNFα production by their blood

macrophages 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 ce ...

in response to stimulation with

IFNγ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

. Furthermore, all lacked expression of IFNγR's on their blood monocytes or lymphocytes, and each was found to have a mutation in the gene on chromosome 6q22-q23 that encodes IFNγR1. Of interest, these children did not appear to be susceptible to infection with agents other than mycobacteria. Th1 responses appeared to be normal in these patients. The susceptibility of these children to mycobacterial infections thus apparently results from an intrinsic impairment of the IFNγ pathway response to these particular intracellular pathogens, showing that IFNγ is obligatory for efficient macrophage antimycobacterial activity. Since the initial discoveries of IFNγR1-deficient humans, many more examples have been found, and IFNγR2-deficient individuals have been found as well.Newport MJ, Holland SM, Levin M, et al. Inherited disorders of the interleukin-12/23-interferon gamma axis. In: Ochs HD, Smith CIE, Puck JM, e eds. Primary immunodeficiency diseases: a molecular and genetic approach. Oxford: Oxford University Press, 2007: 390–401.

Structure and function

Disease linkage

Mutations

References

See also