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Interaction between the components of the interferon gamma receptor complex
S V Kotenko1, L S Izotova, B P Pollack
1Human Genome Sciences, Rockville, Maryland 20850-3338, USA.
Insights
Interferon gamma (IFN-gamma) signaling requires both IFN-gamma receptor 1 (IFN-gamma R1) and IFN-gamma R2. The intracellular domain of IFN-gamma R2 is essential for IFN-gamma-induced signal transduction and receptor component activation.
Area of Science:
- Immunology
- Cellular Signaling
- Molecular Biology
Background:
- Interferon gamma (IFN-gamma) mediates cellular responses through a receptor complex.
- This complex comprises IFN-gamma receptor 1 (IFN-gamma R1) and IFN-gamma receptor 2 (IFN-gamma R2).
- IFN-gamma R2 is known to be crucial for signal transduction.
Purpose of the Study:
- To investigate the functional roles of IFN-gamma receptor components in signal transduction.
- To determine the necessity of IFN-gamma R2's intracellular domain for IFN-gamma signaling.
- To elucidate the interaction between IFN-gamma R1, IFN-gamma R2, and downstream signaling molecules.
Main Methods:
- Utilized cell lines expressing various cloned components of the IFN-gamma receptor complex.
- Employed cross-linking techniques to identify receptor-ligand complexes.
- Assessed signal transduction by measuring MHC class I antigen induction and kinase activation (Jak1, Jak2, Stat1 alpha).
Main Results:
- A specific IFN-gamma R2:IFN-gamma complex was observed, confirming IFN-gamma R2 interaction with IFN-gamma and association with IFN-gamma R1.
- Cells expressing IFN-gamma R1 alone or with a truncated IFN-gamma R2 (lacking key intracellular residues) were unresponsive to IFN-gamma.
- Activation of Jak1, Jak2, Stat1 alpha, and phosphorylation of IFN-gamma R1 occurred only when both IFN-gamma R1 and IFN-gamma R2 were coexpressed.
- Jak2 kinase was found to associate with the intracellular domain of IFN-gamma R2.
Conclusions:
- The intracellular domain of IFN-gamma R2 is indispensable for IFN-gamma signal transduction.
- Both IFN-gamma R1 and IFN-gamma R2 are required for IFN-gamma-mediated signaling events, including MHC class I induction.
- IFN-gamma R2 plays a critical role in recruiting and activating downstream signaling kinases like Jak2.
Abstract:
Interferon gamma (IFN-gamma) signals through a multimeric receptor complex consisting of two different chains: the IFN-gamma receptor binding subunit (IFN-gamma R, IFN-gamma R1), and a transmembrane accessory factor (AF-1, IFN-gamma R2) necessary for signal transduction. Using cell lines expressing different cloned components of the IFN-gamma receptor complex, we examined the function of the receptor components in signal transduction upon IFN-gamma treatment. A specific IFN-gamma R2:IFN-gamma cross-linked complex was observed in cells expressing both IFN-gamma R1 and IFN-gamma R2 indicating that IFN-gamma R2 (AF-1) interacts with IFN-gamma and is closely associated with IFN-gamma R1. We show that the intracellular domain of IFN-gamma R2 is necessary for signaling. Cells coexpressing IFN-gamma R1 and truncated IFN-gamma R2, lacking the COOH-terminal 51 amino acids (residues 286-337), or cells expressing IFN-gamma R1 alone were unresponsive to IFN-gamma treatment as measured by MHC class I antigen induction. Jak1, Jak2, and Stat1 alpha were activated, and IFN-gamma R1 was phosphorylated only in cells expressing both IFN-gamma R1 and IFN-gamma R2. Jak2 kinase was shown to associate with the intracellular domain of the IFN-gamma R2.