Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon

Zhou, Qienyuan; Lavorgna, Alfonso; Bowman, Melissa; Hiscott, John; Harhaj, Edward W.

doi:10.1074/jbc.m114.633065

Cited by 33 publications

(32 citation statements)

References 74 publications

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“…We repeated experiments using poly I:C, an IRF3-stimulating agent that stimulates TBK1 activation via RIG-I, MDA-5 and TLR3 (36, 37). Because 293T cells do not express high levels of TLR3, a 293T cell line stably over-expressing TLR3 (293T-TLR3) was used to ensure robust IRF3 signaling upon incubation with poly I:C. The 293T-based cell line was used because of its high transfection efficiency rate and its common use in studying IRF activation pathways (11, 14, 21, 38). cFLIP L , like MC159, also inhibited IRF3-controlled luciferase activity under this condition (Fig.…”

Section: Resultsmentioning

confidence: 99%

cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

Gates

Shisler

2016

The Journal of Immunology

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Type I interferon (IFN) induction is critical for anti-viral and anti-cancer defenses. Proper down-regulation of type I IFN is equally important to avoid deleterious imbalances in the immune response. The cellular FLIP long isoform protein (cFLIPL) controls type I IFN production, but opposing publications show it as either an inhibitor or inducer of type I IFN synthesis. Regardless, the mechanistic basis for cFLIPL regulation is unknown. Because cFLIPL is important in immune cell development and proliferation, and is a target for cancer therapies, it is important to identify how cFLIPL regulates type I IFN production. Data here show that cFLIPL inhibits IRF3, a transcription factor central for IFNβ and ISG expression. This inhibition occurs during virus infection, cellular exposure to poly I:C or TBK1 over-expression. This inhibition is independent of capase-8 activity. cFLIPL binds to IRF3 and disrupts IRF3 interaction with its IFNβ promoter and its co-activator protein (CBP). Mutational analyses reveal that cFLIPL nuclear localization is necessary and sufficient for inhibitory function. This suggests that nuclear cFLIPL prevents IRF3 enhanceosome formation. Unlike other cellular IRF3 inhibitors, cFLIPL did not degrade or dephosphorylate IRF3. Thus, cFLIPL represents a different cellular strategy to inhibit type I IFN production. This new cFLIPL function must be considered to accurately understand how cFLIPL affects immune system development and regulation.

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Section: Resultsmentioning

confidence: 99%

cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

Gates

Shisler

2016

The Journal of Immunology

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“…For transient expression in MEFs, cells were transfected with plasmids encoding HA at a concentration of 500 ng/ml or 1,000 ng/ml or NA at 1,000 ng/ml using GenJet In Vitro DNA Transfection Reagent for MEFs (Ver. II) (SignaGen Laboratories) (48,49), according to the protocol recommended by the manufacturer. Briefly, the transfection complex was prepared at a ratio of GenJet to DNA of 3:1 (in microliters).…”

Section: Virus and Cellsmentioning

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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“…3A). Phospho-IRF7 was also observed when AIP was expressed in cells, and this was expected because AIP inhibits IRF7 activation downstream of IRF7 phosphorylation (24). In contrast, IRF7 phosphorylation was not detected in cFLIP L -expressing cells (Fig.…”

Section: Cflip L Inhibits Ikk␣-mediated Irf7 Phosphorylationmentioning

confidence: 80%

“…It was unlikely that this lack of detection was due to suboptimal conditions for protein-protein interactions because we detected IRF7 interacting with a known binding partner (AIP) ( Fig. 2A, left panel) (24). Also, we detected cFLIP L interacting with IRF3, a known cFLIP L binding partner ( Fig.…”

Section: Cflip L Does Not Associate With Irf7mentioning

confidence: 86%

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Cellular FLIP long isoform (cFLIPL)–IKKα interactions inhibit IRF7 activation, representing a new cellular strategy to inhibit IFNα expression

Gates-Tanzer

Shisler

2018

Journal of Biological Chemistry

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Interferon α (IFNα) is important for antiviral and anticancer defenses. However, overproduction is associated with autoimmune disorders. Thus, the cell must precisely up- and down-regulate IFNα to achieve immune system homeostasis. The cellular FLICE-like inhibitory protein (cFLIP) is reported to inhibit IFNα production. However, the mechanism for this antagonism remained unknown. The goal here was to identify this mechanism. Here we examined the signal transduction events that occur during TLR9-induced IRF7 activation. The cFLIP long isoform (cFLIP) inhibited the expression of IRF7-controlled natural or synthetic genes in several cell lines, including those with abundant IRF7 protein levels ( dendritic cells). cFLIP inhibited IRF7 phosphorylation; however, cFLIP-IRF7 interactions were not detectable, implying that cFLIP acted upstream of IRF7 dimerization. Interestingly, cFLIP co-immunoprecipitated with IKKα, and these interactions correlated with a loss of IKKα-IRF7 interactions. Thus, cFLIP appears to bind to IKKα to prevent IKKα from phosphorylating and activating IRF7. To the best of our knowledge, this is the first report of a cellular protein that uses this approach to inhibit IRF7 activation. Perhaps this cFLIP property could be engineered to minimize the deleterious effects of IFNα expression that occur during certain autoimmune disorders.

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Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon

Cited by 33 publications

References 74 publications

cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

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

Cellular FLIP long isoform (cFLIPL)–IKKα interactions inhibit IRF7 activation, representing a new cellular strategy to inhibit IFNα expression

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