Preassembly and ligand-induced restructuring of the chains of the IFN-γ receptor complex: the roles of Jak kinases, Stat1 and the receptor chains

Abstract

We previously demonstrated using noninvasive technologies that the interferon-gamma (IFN-γ) receptor complex is preassembled [1]. In this report we determined how the receptor complex is preassembled and how the ligand-mediated conformational changes occur. The interaction of Stat1 with IFN-γR1 results in a conformational change localized to IFN-γR1. Jak1 but not Jak2 is required for the two chains of the IFN-γ receptor complex (IFN-γR1 and IFN-γR2) to interact; however, the presence of both Jak1 and Jak2 is required to see any ligand-dependant conformational change. Two IFN-γR2 chains interact through species-specific determinants in their extracellular domains. Finally, these determinants also participate in the interaction of IFN-γR2 with IFN-γR1. These results agree with a detailed model of the IFN-γ receptor that requires the receptor chains to be pre-associated constitutively for the receptor to be active.

Interferon γ Attenuates Insulin Signaling, Lipid Storage, and Differentiation in Human Adipocytes via Activation of the JAK/STAT Pathway

“…Furthermore, leptin induced a distinct response in human adipocytes relative to IFN␥ with a modest effect on markers of differentiation and no suppression of lipid storage. Given that STAT1 interacts with the IFN␥R1 subunit that is directly bound to JAK1 (51) and that specific activators of JAK2 induce only minimal STAT1 phosphorylation (32)(33)(34), these findings provide further evidence that JAK1-STAT1 activation plays the major role in mediating IFN␥ effects on human adipocytes. Indeed, recent in vivo studies demonstrating that exanatide, a JAK1-STAT1 inhibitor, prevents high fat diet-induced insulin resistance and glucose intolerance in rats (52) strongly suggest an important role for this pathway in diet-induced insulin resistance.…”

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

“…The very low sequence conservation for IFNAR1 is in line with the findings of this study that the TMD and its immediate surroundings serve merely as a bridge between the extracellular and cytoplasmic domain that does not convey a structural signal. This is fundamentally different from the suggested mechanism of EPOR, IL6R2, and VEGFR2 activation, where ligand-induced structural perturbations of the intracellular domains were suggested to play a key role in signaling (26,28,32).…”

Modulation of the activation of Stat1 by the interferon-γ receptor complex

“…Because IFN-γR2 is constitutively preassociated to IFN-γR1 [3], some element in the intracellular domain of IFN-γR2 is allowing IFN-γR1 to remain stably associated with IFN-γR2. This element cannot be the Jak2 association site or Jak2 because (1) Tyk2 could functionally substitute for Jak2 without altering the activation of Stat1 in HeLa cells ( Figure 1D) or in hamster 16-9 cells [61], and (2) destruction of the Jak2 association site did not alter the constitutive interactions between IFN-γR1 and IFN-γR2 [93]. There are sections of the IFN-γR2 intracellular domain that are conserved in evolution but are not involved in interactions with Jak2, such as Leu ; these regions may be required in the interaction with IFN-γR1 and therefore the constitutive interaction between IFN-γR1 and IFN-γR2.…”