PKR-dependent cytosolic cGAS foci are necessary for intracellular DNA sensing

Hu, Siqi; Sun, Hong; Yin, Lijuan; Li, Jian; Mei, Shan; Xu, Feifei; Wu, Chao; Liu, Xiaoman; Zhao, Fei; Zhang, Di; Yu, Haibin; Ren, Lili; Cen, Shan; Wang, Jianwei; Liang, Chen; Guo, Fei

doi:10.1126/scisignal.aav7934

Cited by 53 publications

(48 citation statements)

References 77 publications

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“…cGAS together with G3BP1 was shown to form a complex with PKR, which is important for cGAS activation and IFN production upon dsDNA exposure. Vice versa, PKR was also activated within the complex [204]. Interactions of PKR with immune-related transcription factors, including STAT1 [205] and STAT3 [206], have also been reported.…”

Section: Impact Of Stress Kinases On Innate Immune Signaling Pathwaysmentioning

confidence: 95%

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

Eiermann

Haneke

Sun

et al. 2020

Viruses

100

117

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Cells have evolved highly specialized sentinels that detect viral infection and elicit an antiviral response. Among these, the stress-sensing protein kinase R, which is activated by double-stranded RNA, mediates suppression of the host translation machinery as a strategy to limit viral replication. Non-translating mRNAs rapidly condensate by phase separation into cytosolic stress granules, together with numerous RNA-binding proteins and components of signal transduction pathways. Growing evidence suggests that the integrated stress response, and stress granules in particular, contribute to antiviral defense. This review summarizes the current understanding of how stress and innate immune signaling act in concert to mount an effective response against virus infection, with a particular focus on the potential role of stress granules in the coordination of antiviral signaling cascades.

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Section: Impact Of Stress Kinases On Innate Immune Signaling Pathwaysmentioning

confidence: 95%

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

Eiermann

Haneke

Sun

et al. 2020

Viruses

100

117

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“…proposed to play a role in antiviral signaling (34) by recruiting antiviral proteins including PKR, Rig-I, MDA5, OAS, RNase L, Trim5, ADAR1, ZAP, cGAS and RNA helicases like DHX36, DDX3 and DDX6 (35)(36)(37)(38). Assembly of avSG was required for signaling to produce IFN during NDV, IAV and SINV infections.…”

Section: Downloaded Frommentioning

confidence: 99%

RNase L Amplifies Interferon Signaling by Inducing Protein Kinase R-Mediated Antiviral Stress Granules

Manivannan

Siddiqui

Malathi

2020

J Virol

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Virus infection leads to activation of the interferon (IFN)-induced endoribonuclease RNase L, which results in degradation of viral and cellular RNAs. Both cellular and viral RNA cleavage products of RNase L bind pattern recognition receptors (PRRs), like retinoic acid-inducible I (Rig-I) and melanoma differentiation-associated protein 5 (MDA5), to further amplify IFN production and antiviral response. Although much is known about the mechanics of ligand binding and PRR activation, how cells coordinate RNA sensing with signaling response and interferon production remains unclear. We show that RNA cleavage products of RNase L activity induce the formation of antiviral stress granules (avSGs) by regulating activation of double-stranded RNA (dsRNA)-dependent protein kinase R (PKR) and recruit the antiviral proteins Rig-I, PKR, OAS, and RNase L to avSGs. Biochemical analysis of purified avSGs showed interaction of a key stress granule protein, G3BP1, with only PKR and Rig-I and not with OAS or RNase L. AvSG assembly during RNase L activation is required for IRF3-mediated IFN production, but not IFN signaling or proinflammatory cytokine induction. Consequently, cells lacking avSG formation or RNase L signaling produced less IFN and showed higher susceptibility during Sendai virus infection, demonstrating the importance of avSGs in RNase L-mediated host defense. We propose a role during viral infection for RNase L-cleaved RNAs in inducing avSGs containing antiviral proteins to provide a platform for efficient interaction of RNA ligands with pattern recognition receptors to enhance IFN production to mount an effective antiviral response. IMPORTANCE Double-stranded RNAs produced during viral infections serve as pathogen-associated molecular patterns (PAMPs) and bind pattern recognition receptors to stimulate IFN production. RNase L is an IFN-regulated endoribonuclease that is activated in virus-infected cells and cleaves single-stranded viral and cellular RNAs. The RNase L-cleaved dsRNAs signal to Rig-like helicases to amplify IFN production. This study identifies a novel role of antiviral stress granules induced by RNase L as an antiviral signaling hub to coordinate the RNA ligands with cognate receptors to mount an effective host response during viral infections.

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“…Similar to what was reported in the context of infection with numerous RNA viruses (27, 28, 58), we showed that RIG-I accumulates in stress granules upon Asibi infection. PKR, MDA5, LGP2 and the DNA sensor cGAS were also shown to concentrate in stress granules in cells infected with a large panel of RNA and DNA viruses (20, 22–26). However, we were unable to detect neither Asibi RNA nor dsRNA structures in stress granules of infected cells.…”

Section: Discussionmentioning

confidence: 99%

RIG-I and PKR, but not stress granules, mediate the pro-inflammatory response to Yellow fever virus

Beauclair

Streicher

Bruni

et al. 2020

Preprint

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16 17 18 19 20 21 22 23 24 25 26 42 cytokine induction in YFV-infected hepatocytes, in a stress granule-independent manner. Therefore, by 43 showing the uncoupling of the early cytokine response from the stress granules formation, our model 44 challenges the current view by which stress granules are required for the mounting of the acute antiviral 45 response. 46 47 48 in human hepatocytes infected with YFV. We show that YFV infection promotes the formation of 54 cytoplasmic structures, termed stress granules, in a PKR-, but not RIG-I-dependent manner. Whilst stress 55 granules were previously postulated to be essential platforms for immune activation, we found that they are 56 not required for pro-inflammatory mediators' production upon YFV infection. Collectively, our work 57 uncovered molecular events triggered by the replication of YFV, which could prove instrumental in 58 clarifying the pathogenesis of the disease, with possible repercussions on disease management. 59 60 61 101 undergo a conformational change, which allows interaction with the adaptor protein MAVS and 102 subsequent recruitment of signaling complexes that comprises protein kinases such as TBK1, IKKα, 103 IKKβ and IKKε (14). These events lead to the activation and nuclear translocation of the transcription 104 factors IRF3 and NF-κB, which stimulate the rapid expression of pro-inflammatory cytokines and type 105 I interferons (IFNs). 106 RIG-I plays an important role in initiating the IFN-mediated antiviral response against DENV and 107 ZIKV (15-18). Induction of cytokines upon infection with the vaccine strain of YFV is also mediated 108 129 antiviral nature (27, 28, 30). Here, we investigated the role of RIG-I, PKR and stress granules in the 130 induction of inflammatory cytokines upon infection of hepatoma cells with YFV.

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PKR-dependent cytosolic cGAS foci are necessary for intracellular DNA sensing

Cited by 53 publications

References 77 publications

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

RNase L Amplifies Interferon Signaling by Inducing Protein Kinase R-Mediated Antiviral Stress Granules

RIG-I and PKR, but not stress granules, mediate the pro-inflammatory response to Yellow fever virus

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