Virus-Induced Unfolded Protein Response Attenuates Antiviral Defenses via Phosphorylation-Dependent Degradation of the Type I Interferon Receptor

Abstract

Phosphorylation-dependent ubiquitination and degradation of the IFNAR1 chain of Type I interferon (IFN) receptor is regulated by two different pathways one of which is ligand-independent. We report that this pathway is activated by inducers of the endoplasmic reticulum (ER) stress, including viral infection, in a PERK-dependent manner. Upon infection, activation of this pathway promotes phosphorylation-dependent ubiquitination and degradation of IFNAR1, and specifically inhibits Type I IFN signaling and antiviral defenses. Either knock-in of an IFNAR1 mutant insensitive to virus-induced turnover or conditional knockout of PERK prevented ER stress- and virus-induced IFNAR1 degradation while restoring cellular responses to Type I IFN and resistance to viruses. The role of this novel mechanism in pathogenesis of viral infections and therapeutic approaches to their treatment is discussed.

Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

“…37 Alternatively, basal phosphorylation of Ser535 by CK1␣ 38 is shown to be augmented by a priming site (Ser532) phosphorylation, which can be promoted by signaling stimulated by inducers of unfolded protein responses such as thapsigargin. 23,26 Degron phosphorylation on Ser535 within IFNAR1 was noticeably decreased in the KT1 and KU812 CML cell lines ( Figure 2C-D) and in primary CML cells ( Figure 2E) after treatment with IM, indicating that Bcr-abl signaling may stimulate IFNAR1 turnover via triggering its degron phosphorylation.…”

“…37 Alternatively, basal phosphorylation of Ser535 by CK1␣ 38 is shown to be augmented by a priming site (Ser532) phosphorylation, which can be promoted by signaling stimulated by inducers of unfolded protein responses such as thapsigargin. 23,26 Degron phosphorylation on Ser535 within IFNAR1 was noticeably decreased in the KT1 and KU812 CML cell lines ( Figure 2C-D) and in primary CML cells ( Figure 2E) after treatment with IM, indicating that Bcr-abl signaling may stimulate IFNAR1 turnover via triggering its degron phosphorylation.Indeed, expression of catalytically active (but not kinasedeficient) Bcr-abl in HeLa cells stimulated phosphorylation of endogenous IFNAR1 on Ser535 and decreased the total levels of endogenous IFNAR1 or coexpressed wild-type FLAG-IFNAR1 ( Figure 3A; supplemental Figure 2). The latter effect was not seen on FLAG-IFNAR1 S535A mutant (supplemental Figure 2), suggesting that phosphorylation of the IFNAR1 degron is required for Bcr-abl-stimulated down-regulation of this protein.…”

“…Lentiviral-mediated knockdown was carried out as described previously. 23 For stable transduction, cells were selected in the media containing either puromycin (2 g/mL) or hygromycin (10 g/mL). HeLa cells were transfected by Lipofectamine 2000 (Invitrogen) using standard transfection protocols.…”

Vascular endothelial growth factor–induced elimination of the type 1 interferon receptor is required for efficient angiogenesis

“…Murine ES cells, in which one wild-type Ifnar1 allele has been replaced with the mutant that lacks Ser526, 17 were used to generate knock-in mice that express the mIFNAR1 S526A mutant ("SA"). Bone marrow-derived CD31-positive cells from wild-type mice displayed a noticeable decrease in the cell surface levels of IFNAR1 on treatment with murine VEGF ( Figure 2B).…”

“…[13][14][15][16] Mice with a Ser526Ala substitution within IFNAR1 were generated using previously characterized ES cells. 17 All experiments were conducted with the approval of the University of Pennsylvania Institutional Animal Care and Use Committee. Matrigel Plug assays in WT/WT and heterozygous WT/S526A mice (6-9 weeks old, n ϭ 5 per group) were carried out as described elsewhere.…”