Critical Role of an Antiviral Stress Granule Containing RIG-I and PKR in Viral Detection and Innate Immunity

Onomoto, Koji; Jogi, Michihiko; Yoo, Ji‐Seung; Narita, Ryo; Morimoto, Shiho; Takemura, Azumi; Sambhara, Suryaprakash; Kawaguchi, Akiko; Osari, Suguru; Nagata, Kyosuke; Matsumiya, Tomoh; Namiki, Hideo; Yoneyama, Mitsutoshi; Fujita, Takashi

doi:10.1371/journal.pone.0043031

Cited by 303 publications

(453 citation statements)

References 57 publications

(57 reference statements)

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“…40,41 Interestingly, EIF2AK4 gene expression has been directly correlated with potent CD8 1 T cell responses generated by vaccination. 42 In addition to the antigen-independent modulation of the transcriptome as well as the induction of pro-inflammatory cytokines and chemokines at the injection site, the adjuvant also induced beneficial changes in the dLNs.…”

Section: Rnadjuvantmentioning

confidence: 99%

A novel RNA‐based adjuvant combines strong immunostimulatory capacities with a favorable safety profile

Heidenreich

Jasny

Kowalczyk

et al. 2015

Intl Journal of Cancer

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Protein-and peptide-based tumor vaccines depend on strong adjuvants to induce potent immune responses. Here, we demonstrated that a recently developed novel adjuvant based on a non-coding, long-chain RNA molecule, termed RNAdjuvant V R , profoundly increased immunogenicity of both antigen formats. RNAdjuvant V R induced balanced, long-lasting immune responses that resulted in a strong anti-tumor activity. A direct comparison to Poly(I:C) showed superior efficacy of our adjuvant to enhance antigen-specific multifunctional CD81 T-cell responses and mediate anti-tumor responses induced by peptide derived from HPV-16 E7 protein in the syngeneic TC-1 tumor, a murine model of human HPV-induced cervical cancer. Moreover, the adjuvant was able to induce functional memory responses that mediated complete tumor remission. Despite its remarkable immunostimulatory activity, our RNA-based adjuvant exhibited an excellent pre-clinical safety profile. It acted only locally at the injection site where it elicited a transient but strong up-regulation of pro-inflammatory and anti-viral cytokines as well as cytoplasmic RNA sensors without systemic cytokine release. This was followed by the activation of immune cells in the draining lymph nodes. Our data indicate that our RNA-based adjuvant is a safe and potent immunostimulator that may profoundly improve the efficacy of a variety of cancer vaccines.

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Section: Rnadjuvantmentioning

confidence: 99%

A novel RNA‐based adjuvant combines strong immunostimulatory capacities with a favorable safety profile

Heidenreich

Jasny

Kowalczyk

et al. 2015

Intl Journal of Cancer

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“…Activation of PKR is required for the formation of stress granules in response to virus infection (34)(35)(36)54). This study attempts to delineate the mechanism of NF90 antiviral activity through examination of NF90 involvement in PKR activation and formation of antiviral stress granules using the influenza A virus-infection model.…”

Section: /2mentioning

confidence: 99%

“…Interaction between influenza A virus and host stress granules was demonstrated recently (33,34). Activation of PKR to induce the formation of stress granules is regarded as a hallmark of the cellular response to virus infection (34)(35)(36). This study explored the possibility of NF90 involvement in PKR activation and the formation of stress granules in response to dsRNA treatment or virus infection of cells.…”

mentioning

confidence: 98%

NF90 Exerts Antiviral Activity through Regulation of PKR Phosphorylation and Stress Granules in Infected Cells

Wen

Huang

Mok

et al. 2014

The Journal of Immunology

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NF90 was shown to exhibit broad antiviral activity against several viruses, but detailed mechanisms remain unclear. In this study, we examined the molecular basis for the inhibitory effect of NF90 on virus replication mediated through protein kinase (PKR)-associated translational regulation. We first verified the interaction between NF90 and PKR in mammalian cells and showed that NF90 interacts with PKR through its C-terminal and that the interaction is independent of NF90 RNA-binding properties. We further showed that knockdown of NF90 resulted in significantly lower levels of PKR phosphorylation in response to dsRNA induction and influenza virus infection. We also showed that high concentrations of NF90 exhibit negative regulatory effects on PKR phosphorylation, presumably through competition for dsRNA via the C-terminal RNA-binding domain. PKR activation is essential for the formation of stress granules in response to dsRNA induction. Our results showed that NF90 is a component of stress granules. In NF90-knockdown cells, dsRNA treatment induced significantly lower levels of stress granules than in control cells. Further evidence for an NF90–PKR antiviral pathway was obtained using an NS1 mutated influenza A virus specifically attenuated in its ability to inhibit PKR activation. This mutant virus replicated indistinguishably from wild-type virus in NF90-knockdown cells, but not in scrambled control cells or Vero cells, indicating that NF90’s antiviral function occurs through interaction with PKR. Taken together, these results reveal a yet-to-be defined host antiviral mechanism in which NF90 upregulation of PKR phosphorylation restricts virus infection.

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“…4 A number of studies have linked the transcriptional programs activated by innate immune responses with integrated stress response (ISR) that includes endoplasmic reticulum (ER) stress and unfolded protein response (UPR). [5][6][7][8][9][10] In addition to the induction of IFNs, viral infections also trigger ER stress response. [11][12][13][14][15] A best-studied stress-responsive signaling pathway is the UPR.…”

Section: Introductionmentioning

confidence: 99%

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Ishaq

Natarajan

2016

Signal Transduction Insights

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Supraphysiological concentrations (SPCs) of triiodo-l-thyronine (T3) have been used in the treatment of a number of nonviral diseases. However, the signaling mechanisms that regulate the function of T3 at these concentrations and their role in modulating cellular stress pathways and antiviral responses are unknown. Here, we have investigated the effects of SPCs of T3 on integrated stress response (ISR) signaling pathways and the replication of vesicular stomatitis virus (VSV). T3 amplified Poly IC-induced activation of RNA-dependent protein kinase, induced phosphorylation of eIF2α, stress granule (SG) formation, IRE1α phosphorylation, XBP1 splicing, and the expression of stress markers. T3 inhibited VSV replication by modulating SG formation and the expression of stress response markers. ISR activator guanabenz also inhibited VSV replication and amplified T3-induced anti-VSV response. To summarize, we have uncovered novel functions of T3 at SPCs as an activator of ISR signaling pathways and an inhibitor of VSV replication. This study offers a proof of principle of the concept that ISR activating agents like SPC of T3 and guanabenz can be potential antiviral agents.

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Critical Role of an Antiviral Stress Granule Containing RIG-I and PKR in Viral Detection and Innate Immunity

Cited by 303 publications

References 57 publications

A novel RNA‐based adjuvant combines strong immunostimulatory capacities with a favorable safety profile

A novel RNA‐based adjuvant combines strong immunostimulatory capacities with a favorable safety profile

NF90 Exerts Antiviral Activity through Regulation of PKR Phosphorylation and Stress Granules in Infected Cells

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

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