5 years ago

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

Gullick, Masa, Weathington, Lear, Londino, Chen, Suber, Mallampalli
The IFN gamma receptor 1 (IFNGR1) binds IFN gamma and activates gene transcription pathways crucial for controlling bacterial and viral infections. Although decreases in IFNGR1 surface levels have been demonstrated to inhibit IFN gamma 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 (GSK3 beta) destabilized IFNGR1 while overexpression of GSK3 beta 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 phosphorylation and decreased STAT1-dependent gene induction. Thus, IFNGR1 undergoes rapid site-specific polyubiquitination, a process modulated by GSK3 beta. Ubiquitination appears to be necessary for efficient IFNGR1 dependent gamma gene induction and represents a relatively uncharacterized regulatory mechanism for this receptor.

Publisher URL: http://doi.org/10.1042/BCJ20170548

DOI: 10.1042/BCJ20170548

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