Post-translational modification of the interferon-gamma receptor alters its stability and signaling

Abstract

The IFN gamma receptor 1 (IFNGR1) binds IFN-γ and activates gene transcription path ways crucial for controlling bacterial and viral infections. Although decreases in IFNGR1 surface levels have been demonstrated to inhibit IFN-γ signaling, little is known regarding the molecular mechanisms controlling receptor stability. Here, we show in epithelial and monocytic cell lines that IFNGR1 displays K48 polyubiquitination, is proteasomally degraded, and harbors three ubiquitin acceptor sites at K277, K279, and K285. Inhibition of glycogen synthase kinase 3 beta (GSK3β) destabilized IFNGR1 while overexpression of GSK3β increased receptor stability. We identified critical serine and threonine residues juxtaposed to ubiquitin acceptor sites that impacted IFNGR1 stability. In CRISPR–Cas9 IFNGR1 generated knockout cell lines, cellular expression of IFNGR1 plasmids encoding ubiquitin acceptor site mutations demonstrated significantly impaired STAT1 phosphoryl ation and decreased STAT1-dependent gene induction. Thus, IFNGR1 undergoes rapid site-specific polyubiquitination, a process modulated by GSK3β. Ubiquitination appears to be necessary for efficient IFNGR1-dependent gamma gene induction and represents a relatively uncharacterized regulatory mechanism for this receptor.

Loss of Ubiquitin Ligase STUB1 Amplifies IFNγ-R1/JAK1 Signaling and Sensitizes Tumors to IFNγ

“…STUB1 acts by mediating proteasomal degradation of its core components, IFNγ-R1 and its interaction partner JAK1. Our results suggest that STUB1 is a conserved E3 ubiquitin ligase for both IFNγ-R1 and JAK1, extending a previous observation on the ubiquitination of IFNγ-R1 42 . While STUB1 loss stabilizes cell surface IFNγ-R1, it also increases the abundance of JAK1.…”

Interferon‐γ Receptor 1 and GluR1 upregulated in motor neurons of symptomatic hSOD1G93A mice

“…IFNGR1 expression can be enhanced by proinflammatory cytokines like TNF‐α (Tumor Necrosis Factor‐α) and Interleukin‐1β, which are elevated at early stages in hSOD1G93A mice (Michaelson et al., ). Additionally, post‐translational modifications could potentially be elevated in hSOD1G93A mice that lead to receptor stability (Londino et al., ). These studies, also, explain the reason for lack of enhanced IFNGR1 expression in embryonic hSOD1G93A motor neurons.…”

Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

“…The receptor for IFN-γ is comprised of two IFNGR1 chains and two IFNGR2 chains. IFNGR1 is expressed on most cells at moderate levels, while IFNGR2 is expressed at lower levels; however, IFNGR2 expression can be regulated in specific cell types (Bach, Aguet, & Schreiber, 1997;Bernabei et al, 2001;Fenimore, 2016;Green, Young, & Valencia, 2017;Londino et al, 2017). Ifng −/− and Ifngr1 −/− mice develop normally and have a typical immune system, but both genotypes have defects in resistance to some infectious agents, including mycobacterial species, some viruses, and bacteria; conversely, the Ifngr1 −/− mice are more resistant to LPS (Car et al, 1994;Nakamura et al, 2000;Schroder, Hertzog, Ravasi, & Hume, 2004).…”