DHX29 functions as an RNA co-sensor for MDA5-mediated EMCV-specific antiviral immunity

Zhu, Qingyuan; Tan, Peng; Li, Yinyin; Lin, Meng; Li, Chaoran; Mao, Jingrong; Cui, Jun; Zhao, Wei; Wang, Helen Yicheng; Wang, Rongfu

doi:10.1371/journal.ppat.1006886

Cited by 34 publications

(28 citation statements)

References 62 publications

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“…It is possible that the distinct properties of TLR3 and MDA5, and/or the distinctly localized ZFYVE1 in the lumen of endo/lysosomes and cytosol are responsible for the distinct functions of ZFYVE1. Previously, it has been reported that DHX29 acts as a co-sensor of MDA5 for the recognition of viral dsRNA [27]. RAVER1 acts as a coactivator of MDA5-mediated cellular antiviral response by facilitating the binding of MDA5 to its ligand [28].…”

Section: Plos Pathogensmentioning

confidence: 99%

ZFYVE1 negatively regulates MDA5- but not RIG-I-mediated innate antiviral response

Zhong

Zang

et al. 2020

PLoS Pathog

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The retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including RIG-I and melanoma differentiation-associated gene 5 (MDA5), sense cytoplasmic viral RNA and initiate innate antiviral responses. How RIG-I and MDA5 are differentially regulated remains enigmatic. In this study, we identified the guanylate-binding protein (GBP) and zinc-finger FYVE domain-containing protein ZFYVE1 as a negative regulator of MDA5-but not RIG-I-mediated innate antiviral responses. ZFYVE1-deficiency promoted MDA5-but not RIG-I-mediated transcription of downstream antiviral genes. Comparing to wild-type mice, Zfyve1 -/mice were significantly protected from lethality induced by encephalomyocarditis virus (EMCV) that is sensed by MDA5, whereas Zfyve1 -/and Zfyve1 +/+ mice were comparable to death induced by vesicular stomatitis virus (VSV) that is sensed by RIG-I. Mechanistically, ZFYVE1 interacted with MDA5 but not RIG-I. ZFYVE1 bound to viral RNA and decreased the ligand binding and oligomerization of MDA5. These findings suggest that ZFYVE1 acts as a specific negative regulator of MDA5-mediated innate immune responses by inhibiting its ligand binding and oligomerization. Author summaryRIG-I and MDA5 are the main cytosolic sensors for invaded viral RNA. How these sensors are differentially regulated is largely unknown. In this study, we identified ZFYVE1 as a specific regulator of MDA5-but not RIG-I-mediated antiviral responses. ZFYVE1deficiency promotes antiviral immune responses and renders the mice less susceptible to EMCV-induced death. ZFYVE1 interacts with MDA5 and viral dsRNA, and inhibits the ligand binding and oligomerization of MDA5. Our study reveals a negative regulatory mechanism for keeping MDA5 inactive in un-infected cells, which contributes to our understanding on how innate antiviral responses are delicately regulated to avoid immune damage. ) to H. B.S, Q.Y., and C.L. The funders had no role in study patterns (PAMPs) are sensed by pathogen recognition receptors (PRRs). The PRRs then trigger a series of signaling events, leading to the induction of type I interferons (IFNs), proinflammatory cytokines and other downstream antiviral effector proteins. These effectors act to inhibit viral replication, clear the infected cells and facilitate adaptive immune responses [1].During viral infection, viral nucleic acids act as important PAMPs. It has been demonstrated that the membrane-associated Toll-like receptor 3 (TLR3) recognizes extracellular and endosomal viral RNA, whereas the cytosolic viral RNA is detected by retinoic acid-inducible gene-I (RIG-I) like receptors (RLRs), including RIG-I and melanoma differentiation-associated gene 5 (MDA5) [2]. Upon binding to their ligands, RIG-I and MDA5 undergo conformational changes and recruit PP1α/γ for their dephosphorylation, which is followed by their K63-linked polyubiquitination by several E3 ubiquitin ligases [3][4][5][6][7]. The RLRs then form longer filaments on viral RNA and then interact with the mitochondrial adaptor protein VISA (also called MAVS, IPS-1, and...

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Section: Plos Pathogensmentioning

confidence: 99%

ZFYVE1 negatively regulates MDA5- but not RIG-I-mediated innate antiviral response

Zhong

Zang

et al. 2020

PLoS Pathog

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“…However, a more recent study failed to confirm the antiviral function of DDX60 against a broad range of viruses (207), demanding more detailed studies to understand the precise role of DDX60. Additional examples of helicases reported to function in innate immune signaling in response to dsRNA include DHX15 (208), DHX33 (209,210), DHX29 (211,212), DDX3 (213,214), and the complex of DDX1-DDX21-DHX36 (215). Some helicases, such as DDX17, were shown to function as antiviral effectors independent of immune signaling pathways (16), analogous to the reported effector functions of RLRs (61) and DDX60 (206).…”

Section: Helicases (Besides Rlrs and Dicer)mentioning

confidence: 84%

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Hur

2019

Annu. Rev. Immunol.

266

245

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Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms. KeywordsdsRNA; RIG-I-like receptor; protein kinase R; oligoadenylate synthase; dsRNA-dependent adenosine deaminase; RNA interference HHS Public Access

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“…The authors also show that DHX29 binds to MDA5 but not MAVS or RIG-I, and binding could only be detected when MDA5 was activated by EMCV or HMW poly(I:C). Mechanistically, this study demonstrated that DHX29 mediated RNA binding of MDA5 by interacting with MDA5 through its N-terminus and RNA through its DEXD and helicase domains, and that DHX29 promotes formation of MDA5 filaments, which are required for activation ( Zhu et al, 2018 ). DHX29 was also independently described to interact with RIG-I ( Sugimoto et al, 2014 ), although it may be of greater importance for activation of MDA5 ( Zhu et al, 2018 ).…”

Section: Activation Of Mda5 By Cardiovirusesmentioning

confidence: 88%

“…Yet another partner in detecting dsRNA in cardiovirus infection was recently uncovered. A cDNA screen to identify genes involved in regulating IFN signaling revealed that DHX29 expression increased transcription of an IFN-β reporter plasmid in response to high molecular weight (HMW) poly(I:C) ( Zhu et al, 2018 ). Depletion of DHX29 resulted in decreased phosphorylation of TBK1 and IRF-3 in response to HMW poly(I:C) and EMCV as well as decreased production of IFN-β.…”

Section: Activation Of Mda5 By Cardiovirusesmentioning

confidence: 99%

Innate Immune Detection of Cardioviruses and Viral Disruption of Interferon Signaling

2018

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Cardioviruses are members of the Picornaviridae family and infect a variety of mammals, from mice to humans. Replication of cardioviruses produces double stranded RNA that is detected by helicases in the RIG-I-like receptor family and leads to a signaling cascade to produce type I interferon. Like other viruses within Picornaviridae, however, cardioviruses have evolved several mechanisms to inhibit interferon production. In this review, we summarize recent findings that have uncovered several proteins enabling efficient detection of cardiovirus dsRNA and discuss which cell types may be most important for interferon production in vivo. Additionally, we describe how cardiovirus proteins L, 3C and L∗ disrupt interferon production and antagonize the antiviral activity of interferon effector molecules.

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DHX29 functions as an RNA co-sensor for MDA5-mediated EMCV-specific antiviral immunity

Cited by 34 publications

References 62 publications

ZFYVE1 negatively regulates MDA5- but not RIG-I-mediated innate antiviral response

ZFYVE1 negatively regulates MDA5- but not RIG-I-mediated innate antiviral response

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Innate Immune Detection of Cardioviruses and Viral Disruption of Interferon Signaling

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