The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity

Hage, Adam; Bharaj, Preeti; Tol, Sarah van; Giraldo, María Isabel; González-Orozco, María; Valerdi, Karl M; Warren, Abbey N.; Aguilera-Aguirre, Leopoldo; Xie, Xuping; Widen, Steven G.; Moulton, Hong M.; Lee, Benhur; Johnson, Jeffrey R.; Krogan, Nevan J.; Garcı́a-Sastre, Adolfo; Shi, Pei–Yong; Freiberg, Alexander N.; Rajsbaum, Ricardo

doi:10.1016/j.celrep.2022.110434

Cited by 20 publications

(22 citation statements)

References 96 publications

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“…DDX60 overexpression, a gene upregulated after viral infections, which has been shown to bind RIG-I, increasing RIG-I activation, decreased VSV and poliovirus replication ( 60 ). Similarly, DHX15, a gene upregulated after viral infections, which has been shown to bind RIG-I, increasing RIG-I activation, increased encephalomyocarditis virus (EMCV) replication ( 61 ), and the helicases DHX16 and DDX6, two proteins which recognize specific viral RNA to trigger RIG-I-dependent innate antiviral immunity negatively affect IAV, Zika and SARS-CoV-2 ( 62 ) and enterovirus ( 63 ) replication.…”

Section: Discussionmentioning

confidence: 99%

Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation

et al. 2023

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Interferons (IFNs), IFN-stimulated genes (ISGs), and inflammatory cytokines mediate innate immune responses, and are essential to establish an antiviral response. Within the innate immune responses, retinoic acid-inducible gene I (RIG-I) is a key sensor of virus infections, mediating the transcriptional induction of IFNs and inflammatory proteins. Nevertheless, since excessive responses could be detrimental to the host, these responses need to be tightly regulated. In this work, we describe, for the first time, how knocking-down or knocking-out the expression of IFN alpha-inducible protein 6 (IFI6) increases IFN, ISG, and pro-inflammatory cytokine expression after the infections with Influenza A Virus (IAV), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and Sendai Virus (SeV), or poly(I:C) transfection. We also show how overexpression of IFI6 produces the opposite effect, in vitro and in vivo, indicating that IFI6 negatively modulates the induction of innate immune responses. Knocking-out or knocking-down the expression of IFI6 diminishes the production of infectious IAV and SARS-CoV-2, most likely because of its effect on antiviral responses. Importantly, we report a novel interaction of IFI6 with RIG-I, most likely mediated through binding to RNA, that affects RIG-I activation, providing a molecular mechanism for the effect of IFI6 on negatively regulating innate immunity. Remarkably, these new functions of IFI6 could be targeted to treat diseases associated with an exacerbated induction of innate immune responses and to combat viral infections, such as IAV and SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation

et al. 2023

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“…DHX15 has been characterized as a sensor for several enteric RNA viruses and control production of IFN-β, IFN-λ3, and IL-18 in IECs ( Kenta et al., 2014 ; Lu et al., 2014 ; Xing et al., 2021 ). Recent study identified DHX16 recognizes specific viral RNA to trigger RIG-I-dependent IFN-β production ( Hage et al., 2022 ).…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 infection of intestinal epithelia cells sensed by RIG-I and DHX-15 evokes innate immune response and immune cross-talk

Zhang

Wang

et al. 2023

Front. Cell. Infect. Microbiol.

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SARS-CoV-2 causes a spectrum of clinical symptoms from respiratory damage to gastrointestinal disorders. Intestinal infection of SARS-CoV-2 triggers immune response. However, the cellular mechanism that how SARS-CoV-2 initiates and induces intestinal immunity is not understood. Here, we exploited SARS-CoV-2-GFP/ΔN trVLP pseudo-virus system and demonstrated that RIG-I and DHX15 are required for sensing SARS-CoV-2 and inducing cellular immune response through MAVS signaling in intestinal epithelial cells (IECs) upon SARS-CoV-2 infection. NLRP6 also engages in the regulation of SARS-CoV-2 immunity by producing IL-18. Furthermore, primary cellular immune response provoked by SARS-CoV-2 in IECs further cascades activation of MAIT cells and produces cytotoxic cytokines including IFN-γ, granzyme B via an IL-18 dependent mechanism. These findings taken together unveil molecular basis of immune recognition in IECs in response to SARS-CoV-2, and provide insights that intestinal immune cross-talk with other immune cells triggers amplified immunity and probably contributes to immunopathogenesis of COVID-19.

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“…not covalently linked to a protein). This interaction with unanchored poly-ubiquitin chains promoted DHX16 interaction with RIG-I and activated downstream signalling [126]. DHX16 depletion in mice showed that DHX16 was necessary for optimal IFN production in vivo , ISG induction and protection against IAV and other viruses, such as ZIKV and SARS-CoV-2 [126].…”

Section: Dhx16mentioning

confidence: 99%

“…This interaction with unanchored poly-ubiquitin chains promoted DHX16 interaction with RIG-I and activated downstream signalling [126]. DHX16 depletion in mice showed that DHX16 was necessary for optimal IFN production in vivo , ISG induction and protection against IAV and other viruses, such as ZIKV and SARS-CoV-2 [126]. Moreover, the E3-ubiquitine ligase TRIM6, which was known to stimulate IFN production by activating IKKε through the synthesis of unanchored K48-polyubiquitin chains [127], was shown to interact with DHX16 and to increase its interaction with unanchored polyubiquitin chains, thereby stimulating its activity.…”

Section: Dhx16mentioning

confidence: 99%

DExH/D-box helicases at the frontline of intrinsic and innate immunity against viral infections

Bonaventure

Goujon

2022

Journal of General Virology

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DExH/D-box helicases are essential nucleic acid and ribonucleoprotein remodelers involved in all aspects of nucleic acid metabolism including replication, gene expression and post-transcriptional modifications. In parallel to their importance in basic cellular functions, DExH/D-box helicases play multiple roles in viral life cycles, with some of them highjacked by viruses or negatively regulating innate immune activation. However, other DExH/D-box helicases have recurrently been highlighted as direct antiviral effectors or as positive regulators of innate immune activation. Innate immunity relies on the ability of Pathogen Recognition Receptors to recognize viral signatures and trigger the production of interferons (IFNs) and pro-inflammatory cytokines. Secreted IFNs interact with their receptors to establish antiviral cellular reprogramming via expression regulation of the interferon-stimulated genes (ISGs). Several DExH/D-box helicases have been reported to act as viral sensors (DDX3, DDX41, DHX9, DDX1/DDX21/DHX36 complex), and others to play roles in innate immune activation (DDX60, DDX60L, DDX23). In contrast, the DDX39A, DDX46, DDX5 and DDX24 helicases act as negative regulators and impede IFN production upon viral infection. Beyond their role in viral sensing, the ISGs DDX60 and DDX60L act as viral inhibitors. Interestingly, the constitutively expressed DEAD-box helicases DDX56, DDX17, DDX42 intrinsically restrict viral replication. Hence, DExH/D-box helicases appear to form a multilayer network of primary and secondary factors involved in both intrinsic and innate antiviral immunity. In this review, we highlight recent findings on the extent of antiviral defences played by helicases and emphasize the need to better understand their immune functions as well as their complex interplay.

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The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity

Cited by 20 publications

References 96 publications

Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation

Interferon alpha inducible protein 6 is a negative regulator of innate immune responses by modulating RIG-I activation

SARS-CoV-2 infection of intestinal epithelia cells sensed by RIG-I and DHX-15 evokes innate immune response and immune cross-talk

DExH/D-box helicases at the frontline of intrinsic and innate immunity against viral infections

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