Interferon-gamma (IFN-gamma) belongs to the type II interferon family and is secreted by activated immune cells-primarily T and NK cells, but also B-cells and APC. INFG exerts its effect on cells by interacting with the specific IFN-gamma receptor (IFNGR). IFNGR consists of two chains, namely IFNGR1 (also known as the IFNGR alpha chain) and IFNGR2 (also known as the IFNGR beta chain). IFNGR1 is the ligand binding receptor and is required but not sufficient for signal transduction, whereas IFNGR2 do not bind IFNG independently but mainly plays a role in IFNG signaling and is generally the limiting factor in IFNG responsiveness. Both IFNGR chains lack intrinsic kinase/phosphatase activity and thus rely on other signaling proteins like Janus-activated kinase 1 (JAK1), JAK2 and Signal transducer and activator of transcription 1 (STAT-1) for signal transduction. IFNGR complex in its resting state is a preformed tetramer and upon IFNG association undergoes a conformational change. This conformational change induces the phosphorylation and activation of JAK1, JAK2, and STAT1 which in turn induces genes containing the gamma-interferon activation sequence (GAS) in the promoter.
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GAF transcription factor translocated into nucleus binds to defined DNA sequence called GAS (gamma activated sequence) elements in the promoters of IFN-gamma responsive elements and initiate transcription.
IFN-gamma stimulates gene expression of about 200 genes which include the primary response genes like IRFs, Fc-gamma receptor (FCGR), GBPs (guanylate-binding proteins) and also major histocompatibility complex (MHC) class I and class II molecules, proteins involved in antigen presentation, antiviral proteins like PKR, OAS proteins etc. A wonderful list of most of the IFN-gamma inducible proteins with corresponding literature are mentioned in the review article and the supplementary document by Boehm et al 1997.
Released GAF complex translocates to the nucleus and binds to the gamma-activated sequence (GAS) element present in the promoters of IFNG-regulated genes and induces the transcription of IFNG-responsive genes.
The initial phosphorylation of JAK1 and JAK2 is mediated by JAK2. Autophosphorylated JAK2 may transphopshorylate JAK1 bound to IFNGR1 chain. Tyrosine 1033 in the activation loop of the JAK1 kinase domain may be the target for transphosphorylation (phosphorylation site mentioned here is based on sequence similarity with all the other JAK kinases).
IFN-gamma binding to the receptor complex, induces JAK2 autophosphorylation and activation. Like all protein tyrosine kinases (PTKs) JAK2 activity also depends on the phosphorylation of tandem tyrosine residues within the activation loop that results in the removal of the activation loop from the active site. Multiple phosphorylation sites have been identified in JAK2 (tyrosines 221, 570, 868, 966, 972, 1007 and 1008 ) of which phosphorylation of tyrosine 1007 is essential for kinase activity. Tyrosine 1007 is in the activation loop and phosphorylation allows access of the catalytic loop to the ATP in the ATP binding domain. Of all the predicted phoshorylation sites only tyrosine 1007 is represented in the reaction.
The phosphorylated tyrosine residue 440 in the 440YDKPH444 motif on IFNGR1 chain serves as a docking site and recruits STAT1, an SH2 domain-containing transcription factor to the functional receptor unit.
STAT1 pair recruited to the receptor complex is phosphorylated near the C-terminus at residue Y701, probably by JAK2. This phosphorylation enables the STAT1 homodimer formation which is further phosphorylated on residue S727.
The phosphorylated active JAK1 kinase inturn phosphorylates tyrosine residue 440 on each of the IFNGR1 chains to form two adjacent docking sites for the latent STAT1 SH2 domains.
The IFNG receptor complex is a pre-assembled entity, as constitutive interactions are seen between IFNGR1 and IFNGR2, and between two IFNGR2 chains in the absence of ligand IFNG. JAK1 and JAK2 constitutively associate with the intracellular domains of the subunits of the IFNG receptor complex, providing it with tyrosine kinase activity. In unstimulated cells JAK1 preferentially associates with IFNGR1 and while JAK2 associates with IFNGR2 chains. JAK1 enhances the interaction between IFNGR1 and IFNGR2 chains, and thus has a major role in the pre-assembly of the IFNGR complex, in contrast the kinase activity of JAK2 is required to observe any signaling by IFNG. IFNG binds directly to both the receptor chains IFNGR1 and IFNGR2. IFNGR1 is a high affinity receptor and binds directly to IFNG whereas IFNGR2 binds to IFNG in presence of IFNGR1. According to Krause et al. model IFNG binds to IFNGR1 chains first and then IFNGR2 chains interact with the IFNGR1:IFNG:IFNGR1 complex.
The phosphorylated STAT1 on IFNGR1 chains homodimerize through reciprocal SH2-phosphotyrosine interactions to form p-STAT1 homodimer called gamma-activated-factor (GAF). This phosphorylated STAT1 homodimer disassociates from the receptor complex and translocates to the nucleus.
SOCS-1 and SOCS-3 coprecipitates with JAK kinases upon IFNG stimulation and are able to inhibit the JAK-STAT pathway, although with different affinity and kinetics. SOCS1 and SOCS3 binds to phosphorylated JAK1/2 and prevent the tyrosine kinase activity of JAKs through their kinase inhibitory region (KIR), thereby inhibiting downstream IFNG signaling. SOCS1 may also prevent IFNG signaling by targeting the signaling machinery to ubiquitin-proteasomal degradation pathway.
PIAS1 protein interacts directly with phoshorylated STAT1 dimers and inhibit the transcriptional activity of STAT1 by blocking the DNA-binding domain of STAT1. It has also been suggested that PIAS proteins might regulate transcription by promoting small ubiquitin-related modifier (SUMO1) conjugation of STAT1. The significance of STAT1 sumoylation in regulating STAT1 activity is controversial and needs to be clarified.
Protein tyrosine phosphatases (PTPs) SHP1 and SHP2 down regulate the IFNG signaling by dephosphorylating the tyrosine residues critical to the activation of JAK kinases. PTP1B interacts directly with JAK2 but not JAK1 and dephosphorylate the tyrosine Y1007 on JAK2.
Kinases like Protein kinase C delta (PKC-delta) and Calcium/calmodulin-dependent protein kinase II (CaMK II ) can phosphorylate STAT1 at serine 727 (S727). This phosphorylation is not required for STAT1 homodimer formation, nuclear translocation and DNA binding. However, it is essential for the full transcriptional activation of STAT1.
The nuclear isoform of T cell protein tyrosine phosphatase (TC-PTP) referred as TC45 (or TC-PTPa) dephosphorylates p-STAT1 dimer in the nucleus. It can also dephosphorylate p-JAK1/3 in IFNG stimulated cells.
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in IFNG-regulated
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in IFNG-regulated
genesIFNG binds directly to both the receptor chains IFNGR1 and IFNGR2. IFNGR1 is a high affinity receptor and binds directly to IFNG whereas IFNGR2 binds to IFNG in presence of IFNGR1. According to Krause et al. model IFNG binds to IFNGR1 chains first and then IFNGR2 chains interact with the IFNGR1:IFNG:IFNGR1 complex.