ELF4 is critical for induction of type I interferon and the host antiviral response

You, Fangtian; Wang, Penghua; Yang, Long; Yang, Guang; Zhao, Yang O.; Qian, Feng; Walker, Wendy E.; Sutton, Richard E.; Montgomery, Ruth R.; Lin, Rongtuan; Iwasaki, Akiko; Fikrig, Erol

doi:10.1038/ni.2756

Cited by 93 publications

(139 citation statements)

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“…ULK1 and ELF4 were recently implicated in the regulation of STING-dependent signaling (39,49). As AMPK has been shown to interact with ULK1 (50), we hypothesized that, in the absence of AMPK, ULK1 would repress STING-dependent signaling.…”

Section: Discussionmentioning

confidence: 99%

“…To confirm that this was caused by an increase in viral replication, VSV-G protein was monitored by Western blot analysis. By 6 h post-infection, VSV-G protein A Previously Identified Regulator of STING Signaling, ULK1, Is Constitutively Dephosphorylated in AMPK-deficient Cells-ULK1 and ELF4 have been demonstrated recently to regulate STING-dependent signaling in opposing fashions: ELF4 enhances STING-dependent signaling by binding to regulatory sites within the IFN-␤ promoter, thereby increasing the binding affinity of IRF3 and IRF7 to interferon-sensitive response elements within the IFN-␤ promoter (49). Conversely, the ULK1 kinase has been reported to inhibit STING-dependent IRF3 phosphorylation by phosphorylating the Ser-366 residue of STING to prevent recruitment of IRF3 (39).…”

Section: Ampk-deficient Mefs Exhibit Impaired Vsv-dependent Ifn-␤ Expmentioning

confidence: 99%

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AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

Prantner

Perkins

Vogel

2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe host protein Stimulator of Interferon Genes (STING) has been shown to be essential for recognition of both viral and intracellular bacterial pathogens, but its regulation remains unclear. Previously, we reported that mitochondrial membrane potential regulates STING-dependent IFN-␤ induction independently of ATP synthesis. Because mitochondrial membrane potential controls calcium homeostasis, and AMP-activated protein kinase (AMPK) is regulated, in part, by intracellular calcium, we postulated that AMPK participates in STING activation; however, its role has yet to be been defined. Addition of an intracellular calcium chelator or an AMPK inhibitor to either mouse macrophages or mouse embryonic fibroblasts (MEFs) suppressed IFN-␤ and TNF-␣ induction following stimulation with the STING-dependent ligand 5,6-dimethyl xanthnone-4-acetic acid (DMXAA). These pharmacological findings were corroborated by showing that MEFs lacking AMPK activity also failed to up-regulate IFN-␤ and TNF-␣ after treatment with DMXAA or the natural STING ligand cyclic GMP-AMP (cGAMP). As a result, AMPK-deficient MEFs exhibit impaired control of vesicular stomatitis virus (VSV), a virus sensed by STING that can cause an influenza-like illness in humans. This impairment could be overcome by pretreatment of AMPK-deficient MEFs with type I IFN, illustrating that de novo production of IFN-␤ in response to VSV plays a key role in antiviral defense during infection. Loss of AMPK also led to dephosphorylation at Ser-555 of the known STING regulator, UNC-51-like kinase 1 (ULK1). However, ULK1-deficient cells responded normally to DMXAA, indicating that AMPK promotes STING-dependent signaling independent of ULK1 in mouse cells.Pathogen sensing by innate immune cells is essential for host defense in response to invading microorganisms. Recognition by pattern recognition receptors typically activates signal transduction pathways, leading to up-regulation of cytokines like TNF-␣ and IFN-␤. Although IFN-␤ has a well established role in defense against viral infection, intracellular bacterial infections also induce this cytokine. In the past decade, our understanding of the molecular basis for these signaling pathways has expanded greatly and it has been discovered that there is some overlap between proteins responsible for recognition of bacteria and virus alike. One particular example is the mitochondrial and endoplasmic reticulum resident protein stimulator of interferon genes (STING) 2 (1-3). STING has been shown to be crucial for recognition of both DNA viruses (4 -6) and intracellular bacterial pathogens (7-12). STING senses DNA viruses indirectly, requiring the host enzyme cyclic GMP-AMP synthase (cGAS) to convert the viral double stranded DNA into the compound cGAMP (13-15). This metazoan second messenger, in turn, binds with high affinity to STING dimers, changing the protein conformation (16), such that it leads to activation of the kinase TBK1 and subsequent phosphorylation of the transcription factor IRF3, which is piv...

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Section: Discussionmentioning

confidence: 99%

Section: Ampk-deficient Mefs Exhibit Impaired Vsv-dependent Ifn-␤ Expmentioning

confidence: 99%

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

Prantner

Perkins

Vogel

2017

Journal of Biological Chemistry

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“…The transcription factors ELF4 and IRF5 both have been implicated as participants in the MAVS-dependent induction of IFN-␤ after WNV infection. A deficiency of ELF4 resulted in reduced type I IFN production after WNV infection in mice (13). ELF4 translocates into the nucleus after MAVS-dependent activation, binds to IFN promoters, and cooperatively increases the binding affinity of IRF3 and IRF7 (13).…”

mentioning

confidence: 99%

Interferon Regulatory Factor 5-Dependent Immune Responses in the Draining Lymph Node Protect against West Nile Virus Infection

Thackray

Shrestha

Richner

et al. 2014

J Virol

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Upon activation of Toll-like and RIG-I-like receptor signaling pathways, the transcription factor IRF5 translocates to the nucleus and induces antiviral immune programs. The recent discovery of a homozygous mutation in the immunoregulatory gene guanine exchange factor dedicator of cytokinesis 2 (Dock2 mu/mu ) in several Irf5 ؊/؊ mouse colonies has complicated interpretation of immune functions previously ascribed to IRF5. To define the antiviral functions of IRF5 in vivo, we infected backcrossed Irf5 ؊/؊ ؋ Dock2 wt/wt mice (here called Irf5 ؊/؊ mice) and independently generated CMV-Cre Irf5 fl/fl mice with West Nile virus (WNV), a pathogenic neurotropic flavivirus. Compared to congenic wild-type animals, Irf5؊/؊ and CMV-Cre Irf5 fl/fl mice were more vulnerable to WNV infection, and this phenotype was associated with increased infection in peripheral organs, which resulted in higher virus titers in the central nervous system. The loss of IRF5, however, was associated with only small differences in the type I interferon response systemically and in the draining lymph node during WNV infection. Instead, lower levels of several other proinflammatory cytokines and chemokines, as well as fewer and less activated immune cells, were detected in the draining lymph node 2 days after WNV infection. WNV-specific antibody responses in Irf5 ؊/؊ mice also were blunted in the context of live or inactivated virus infection and this was associated with fewer antigen-specific memory B cells and long-lived plasma cells. Our results with Irf5 ؊/؊ mice establish a key role for IRF5 in shaping the early innate immune response in the draining lymph node, which impacts the spread of virus infection, optimal B cell immunity, and disease pathogenesis. A canonical model for type I IFN production after virus infection is a two-step positive feedback loop that is regulated by Interferon regulatory factor 3 (IRF3) and IRF7 (1). Detection of viral nucleic acids by Toll-like receptors (TLRs), RIG-I-like (RLRs) receptors, or DNA sensors induces nuclear localization of IRF3, which in concert with NF-B and ATF-2/c-Jun stimulates transcription, synthesis, and secretion of IFN-␤ by infected cells. Extracellular interferon beta (IFN-␤) binds to the type I IFN receptor (IFNAR) and triggers activation of the JAK-STAT signaling pathway and induction of IFN-stimulated genes (ISGs) (2), which inhibit viral entry, translation, replication, and assembly through a variety of independent mechanisms (reviewed in reference 3). While IRF3 is constitutively expressed in many tissues, IRF7 is an ISG required for the expression of most IFN-␣ subtypes and is thus a key mediator of the type I IFN amplification loop (1, 4).Noncanonical signaling pathways also induce type I IFN responses. Even with genetic ablation of IRF3 and IRF7 (Irf3 Ϫ/Ϫ ϫ Irf7 Ϫ/Ϫ double-knockout [DKO] cells or mice), type I IFN was produced after infection with West Nile virus (WNV), dengue virus, murine norovirus, or murine cytomegalovirus, albeit at reduced levels compared to wild-type ...

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“…The group also demonstrated that ELF4 acts as an IFN transcription factor, as it has the potential to increase the binding affinity of IRF3 and IRF7 through cooperative binding to newly identified enhancer elements (EICE) in the IFN promoters. 1 These new findings not only extend our knowledge about the details of the fine-tuning of the innate IFN responses, but also represent a new milestone by describing the role of EICE elements in this process.…”

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confidence: 55%

Finding a fairy in the forest: ELF4, a novel and critical element of type I interferon responses

Szabó

Rajnavölgyi

2014

Cell Mol Immunol

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T ype I interferon (IFN) production is a key event during innate immune responses. This early and prompt mechanism is mediated by multiple factors that involve various pattern recognition receptors (PRRs), adaptor proteins, kinases and transcription factors. Stimulator of IFN genes (STING) is an important transmembrane adaptor protein that plays a role in the activation of downstream transcription factors, such as IFN regulatory factor 3 (IRF3) and signal transducer and activator of transcription 6, via TANKbinding kinase 1 (TBK1), which has been considered the main innate immune defense weaponry against viruses and intracellular pathogens. In a current issue of Nature Immunology, You et al. showed that, after viral infection, the ETS-related transcription factor ELF4 (previously known as MEF) interacts with STING and is consequently activated by TBK1. This process leads to the nuclear translocation of ELF4 and its binding to IFN promoters (Figure 1). The group also demonstrated that ELF4 acts as an IFN transcription factor, as it has the potential to increase the binding affinity of IRF3 and IRF7 through cooperative binding to newly identified enhancer elements (EICE) in the IFN promoters. 1 These new findings not only extend our knowledge about the details of the fine-tuning of the innate IFN responses, but also represent a new milestone by describing the role of EICE elements in this process.Innate immune responses are initiated by invading pathogens through the detection of their evolutionally conserved pathogen-associated molecular patterns. Detection of viral pathogen-associated molecular patterns is carried out by intracellular Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and several other nucleic acid sensors, such as AIM2-like receptors. 2 As a result of pathogenassociated molecular pattern-induced activation, PRRs trigger NF-kB-dependent inflammatory cytokine and chemokine responses and the production of type I IFNs through the activation of IRF3 and IRF7. 3 Type I IFNs are critical components in the establishment of the antiviral state and the resistance of host cells to viral replication. PRRs use different adaptor proteins to link the downstream signals to the NF-kB and IRF transcription factors. A crucial element in these pathways is mitochondrial MAVS (also known as VISA, Cardif or IPS-1), which is an ancient adaptor protein that couples RLRs to NF-kB and promotes TBK1 and IRF3 signaling (Figure 1). Previous studies have revealed that the ETS family transcription factor ELF4 takes part in various cellular processes, such as tumorigenesis, 4 the DNA damage response 5 and cell cycle regulation. 6 Despite the growing body of research in this field, the exact physiological role of ELF4 remained unknown.In their article, You et al. demonstrate that ELF4 is a critical factor in the regulation of type I IFN responses and plays a significant role in the antiviral host defense. ELF4 was shown to interact with STING, as demonstrated by coimmunoprecipitation analysis in HeLa cells. The type I IFN-...

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ELF4 is critical for induction of type I interferon and the host antiviral response

Cited by 93 publications

References 48 publications

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

Interferon Regulatory Factor 5-Dependent Immune Responses in the Draining Lymph Node Protect against West Nile Virus Infection

Finding a fairy in the forest: ELF4, a novel and critical element of type I interferon responses

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