Functional Cartography of the Ectodomain of the Type I Interferon Receptor Subunit ifnar1

Lamken, Peter; Gavutis, Martynas; Peters, Imke; Heyden, José Van der; Uzé, Gilles; Piehler, Jacob

doi:10.1016/j.jmb.2005.05.008

Cited by 49 publications

(57 citation statements)

References 34 publications

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“…We and others have shown that the minimal ligand binding region for IFNs on IFNAR1 generally exists on the three membrane distal subdomains of this receptor (12). More specifically for IFN-␤, we have further shown that the interface spanning both Tyr 240 and Tyr 274 on IFNAR1-SD3 is most vital to IFNAR1 binding and IFN-␤ function.…”

Section: Discussionsupporting

confidence: 61%

“…Furthermore, specific insight into the mode of IFN-␤-mediated activation of IFNAR1 was obtained from the crystal structure of the murine IFN-␤-IFNAR1 complex (11). Comparison of these structures and evidence from the literature (12) suggests that the minimal ligand binding domains for human and mouse IFNAR1 are similar and sit broadly across the three membrane distal SDs (SD1-3) of the receptor with limited involvement of the membrane proximal subdomain, SD4 (Fig. 1A).…”

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confidence: 96%

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A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling

Weerd

Matthews

Pattie

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe interaction of IFN-␤ with its receptor IFNAR1 (interferon ␣/␤ receptor subunit 1) is vital for host-protective anti-viral and anti-proliferative responses, but signaling via this interaction can be detrimental if dysregulated. Whereas it is established that IFNAR1 is an essential component of the IFNAR signaling complex, the key residues underpinning the IFN-␤-IFNAR1 interaction are unknown. Guided by the crystal structure of the IFN-␤-IFNAR1 complex, we used truncation variants and site-directed mutagenesis to investigate domains and residues enabling complexation of IFN-␤ to IFNAR1. We have identified an interface on IFNAR1-subdomain-3 that is differentially utilized by IFN-␤ and IFN-␣ for signal transduction. We used surface plasmon resonance and cell-based assays to investigate this important IFN-␤ binding interface that is centered on IFNAR1 residues Tyr 240 and Tyr The type I IFNs, including 14 IFN-␣ and lone IFN-␤, IFN-⑀, and IFN-, have critical roles in response to viral and bacterial infections and cancers (1, 2). They are also applied clinically for the treatment of hepatitis virus B and C (1), cancers including melanoma (3), and multiple sclerosis (4). Although they show clinical efficacy, their use is restricted by dose-limiting toxicities, including leukopenia, nausea, fatigue, neurological disorders (3), and localized cutaneous effects (5). All type I IFNs engage their cognate receptors, IFNAR1 and IFNAR2, to activate the canonical JAK-STAT signaling pathway, but ligand engagement can also activate alternative signaling pathways (6). Despite sharing these receptor components, there are IFN subtype-specific elements to signaling; compared with IFN-␣, IFN-␤ has specific roles in osteoclastogenesis (7), control of chronic viral infection (8), the potent induction of apoptotic pathways required for control of tumor cell growth, and the development of B cells and myelopoiesis (9).Structural insight into the IFN-IFNAR 5 interactions has been gleaned from the crystal structures of a human IFN-␣2 variant and human IFN-in complex with both IFNAR1 and IFNAR2 (10). Furthermore, specific insight into the mode of IFN-␤-mediated activation of IFNAR1 was obtained from the crystal structure of the murine IFN-␤-IFNAR1 complex (11). Comparison of these structures and evidence from the literature (12) suggests that the minimal ligand binding domains for human and mouse IFNAR1 are similar and sit broadly across the three membrane distal SDs (SD1-3) of the receptor with limited involvement of the membrane proximal subdomain, SD4 (Fig. 1A). It has also been shown that key residues discriminate between ligands and that there is potential for ligand-specific interaction interfaces (10, 11).

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Section: Discussionsupporting

confidence: 61%

mentioning

confidence: 96%

A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling

Weerd

Matthews

Pattie

et al. 2017

Journal of Biological Chemistry

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“…However, transient expression of HA did not affect the size of IFNAR1, suggesting that HA is not responsible for the infection-mediated change of IFNAR1's molecular weight. Since IFNAR1 is glycosylated at multiple sites and palmitoylated (78,79), virus infection may regulate the posttranslational modification process. The mechanism behind this phenomenon needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

Xia

Vijayan

Pritzl

et al. 2016

J Virol

114

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Influenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway. Following infection, the level of IFNAR1 protein, but not mRNA, decreased. Indeed, IFNAR1 was phosphorylated and ubiquitinated by IAV infection, which resulted in IFNAR1 elimination. The transiently overexpressed IFNAR1 displayed antiviral activity by inhibiting virus replication. Importantly, the hemagglutinin (HA) protein of IAV was proved to trigger the ubiquitination of IFNAR1, diminishing the levels of IFNAR1. Further, influenza A viral HA1 subunit, but not HA2 subunit, downregulated IFNAR1. However, viral HA-mediated degradation of IFNAR1 was not caused by the endoplasmic reticulum (ER) stress response. IAV HA robustly reduced cellular sensitivity to type I IFNs, suppressing the activation of STAT1/STAT2 and induction of IFN-stimulated antiviral proteins. Taken together, our findings suggest that IAV HA causes IFNAR1 degradation, which in turn helps the virus escape the powerful innate immune system. Thus, the research elucidated an influenza viral mechanism for eluding the IFNAR signaling pathway, which could provide new insights into the interplay between influenza virus and host innate immunity. IMPORTANCE Influenza A virus (IAV) infection causes significant morbidity and mortality worldwide and remains a major health concern. When triggered by influenza viral infection, host cells produce type I interferon (IFN Influenza virus infection causes seasonal and pandemic influenza with significant morbidity and mortality in humans (1). Outbreaks of avian influenza by highly pathogenic H5N1 and H7N9 viruses have raised the risk for the occurrence of another influenza pandemic (2-4). The genome of influenza A virus (IAV) encodes at least 11 proteins, including hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix proteins (M1 and M2), nonstructural proteins (NS1 and NS2), polymerase proteins (PA, PB1, and PB2), and PB1-F2 (5, 6). Antiviral drugs against influenza that block the function of viral proteins such as NA and M2 were developed to treat the infection. However, because of the high mutability, several strains of seasonal influenza and avian influenza viruses were shown to be resistant to the current antiviral drugs (6-8). Therefore, designing new therapeutics and identifying cellular targets of the infection are important to effectively control influenza.Type I interferons (IFNs), which include multiple IFN-␣ subtypes and IFN-␤, induce the expression of numerous interferonstimulated genes (ISGs) that establish antiviral states (9-11). Therefore, type I IFNs play an important role in the host defense system against viruses, including IAV (12)(13)(14). Influenza v...

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“…It is interesting to consider the potential role of the second IFN-␣ receptor subunit, IFNAR2, that we also show to be palmitoylated. IFNAR2 is the subunit that presents the highest affinity for IFN-␣, and the current model is that the primary interaction at the cell surface is between IFN-␣ and IFNAR2, with the IFNAR2-bound IFN-␣ complex interacting with IFNAR1 being a subsequent event (45,46). However, another study suggests that IFNAR1 and IFNAR2 can also be found pre-associated at the plasma membrane prior to IFN binding (28), a model also described for the two IFN-␥ receptor chains (47).…”

Section: Discussionmentioning

confidence: 99%

Palmitoylation of Interferon-α (IFN-α) Receptor Subunit IFNAR1 Is Required for the Activation of Stat1 and Stat2 by IFN-α

Claudinon

Gonnord

Beslard

et al. 2009

Journal of Biological Chemistry

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Type I interferons (IFNs) bind IFNAR receptors and activate Jak kinases and Stat transcription factors to stimulate the transcription of genes downstream from IFN-stimulated response elements. In this study, we analyze the role of protein palmitoylation, a reversible post-translational lipid modification, in the functional properties of IFNAR. We report that pharmacological inhibition of protein palmitoylation results in severe defects of IFN receptor endocytosis and signaling. We generated mutants of the IFNAR1 subunit of the type I IFN receptor, in which each or both of the two cysteines present in the cytoplasmic domain are replaced by alanines. We show that cysteine 463 of IFNAR1, the more proximal of the two cytoplasmic cysteines, is palmitoylated. A thorough microscopic and biochemical analysis of the palmitoylation-deficient IFNAR1 mutant revealed that IFNAR1 palmitoylation is not required for receptor endocytosis, intracellular distribution, or stability at the cell surface. However, the lack of IFNAR1 palmitoylation affects selectively the activation of Stat2, which results in a lack of efficient Stat1 activation and nuclear translocation and IFN-␣-activated gene transcription. Thus, receptor palmitoylation is a previously undescribed mechanism of regulating signaling activity by type I IFNs in the Jak/Stat pathway.Type I interferons (IFN 7 ␣/␤) are potent cellular mediators essential for several key cell functions, including immunomodulatory, antiviral, and antiproliferative activities. These pleiotropic effects occur through the transcriptional regulation of many IFN-stimulated genes (ISGs) (1). IFN signal transduction relies mainly on the activation of the Janus tyrosine kinase (Jak)/signal-transducing activators of transcription (Stat) pathways, although several other signaling cascades have also been associated with IFN-regulated transcription (2, 3). In general, the binding of type I IFNs to the cell surface receptor IFNAR1 and IFNAR2 subunits induces tyrosine phosphorylation in trans of the IFNAR-associated Jak kinases (Tyk2 with IFNAR1 and Jak1 with IFNAR2), which in turn leads to IFNAR tyrosine phosphorylation. Several members of the Stat family can be activated by type I IFNs, and Stat1 and Stat2 are the main downstream effectors of the type I IFN transcriptional response. Upon IFN-␣ stimulation, cytosolic Stat2 is recruited to the activated IFNAR complex where it becomes tyrosine-phosphorylated by the receptor-associated Jak kinases. Stat2 activation is a key event in IFN-␣ signaling because it is required for the indirect recruitment, through binding to Stat2, of Stat1 to IFNAR1 and its activation. There is some debate as to whether cytosolic Stat2 is preferentially recruited to IFNAR1 or to IFNAR2 (4 -9). Whereas the SH2 domain of Stat2 binds to a region surrounding the phosphorylated tyrosine 466 of IFNAR1, Stat2 can bind to IFNAR2 whether it is tyrosine-phosphorylated or not. This series of sequential tyrosine phosphorylations precedes the translocation of the IFN-stimulated gene factor 3...

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Functional Cartography of the Ectodomain of the Type I Interferon Receptor Subunit ifnar1

Cited by 49 publications

References 34 publications

A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling

A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling

Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

Palmitoylation of Interferon-α (IFN-α) Receptor Subunit IFNAR1 Is Required for the Activation of Stat1 and Stat2 by IFN-α

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