Alphavirus infection triggers antiviral RNAi immunity in mammals

Kong, Jing; Bie, Yuanyuan; Ji, Wenting; Xu, Junchao; Lyu, Bao; Xiong, Xiaobei; Qiu, Yang; Zhou, Xi

doi:10.1016/j.celrep.2023.112441

Cited by 7 publications

(5 citation statements)

References 53 publications

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“…3B , Appendix Fig. S 3B ), in agreement with previous reports (Kong et al, 2023 ; Zhang et al, 2021 ). The relative number of reads that mapped to both strands of the viral RNA was similar in Dicer WT and N1 cells.…”

Section: Resultssupporting

confidence: 92%

The helicase domain of human Dicer prevents RNAi-independent activation of antiviral and inflammatory pathways

Baldaccini,

Gaucherand,

Chane-Woon-Ming

et al. 2024

EMBO J

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In mammalian somatic cells, the relative contribution of RNAi and the type I interferon response during viral infection is unclear. The apparent inefficiency of antiviral RNAi might be due to self-limiting properties and mitigating co-factors of the key enzyme Dicer. In particular, the helicase domain of human Dicer appears to be an important restriction factor of its activity. Here, we study the involvement of several helicase-truncated mutants of human Dicer in the antiviral response. All deletion mutants display a PKR-dependent antiviral phenotype against certain viruses, and one of them, Dicer N1, acts in a completely RNAi-independent manner. Transcriptomic analyses show that many genes from the interferon and inflammatory response pathways are upregulated in Dicer N1 expressing cells. We show that some of these genes are controlled by NF-kB and that blocking this pathway abrogates the antiviral phenotype of Dicer N1. Our findings highlight the crosstalk between Dicer, PKR, and the NF-kB pathway, and suggest that human Dicer may have repurposed its helicase domain to prevent basal activation of antiviral and inflammatory pathways.

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Section: Resultssupporting

confidence: 92%

The helicase domain of human Dicer prevents RNAi-independent activation of antiviral and inflammatory pathways

Baldaccini,

Gaucherand,

Chane-Woon-Ming

et al. 2024

EMBO J

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“…Fig. 2C), in agreement with previous reports (Kong et al, 2023;Zhang et al, 2021). The number of reads that mapped to both strands of the viral RNA was however higher in Dicer WT than in N1 cells.…”

Section: Rna Interference Is Not Involved In Dicer N1 Phenotypesupporting

confidence: 93%

Non-canonical contribution of human Dicer helicase domain in antiviral innate immune response

Baldaccini,

Gaucherand,

Chane-Woon-Ming

et al. 2023

Preprint

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In mammals, the co-existence of RNAi and the type I interferon response in somatic cells begs the question of their compatibility and relative contribution during viral infection. Previous studies provided hints that both mitigating co-factors and self-limiting properties of key proteins such as Dicer could explain the apparent inefficiency of antiviral RNAi. Indeed, the helicase domain of human Dicer limits its processing activity and acts as an interaction platform for co-factors that could hinder its function. We studied the involvement of several helicase-truncated mutants of human Dicer in the antiviral response. We show that all deletion mutants display an antiviral phenotype against alphaviruses and an enterovirus. While only one of them, Dicer N1, is antiviral in an RNAi-independent manner, they all require the expression of PKR to be active. To elucidate the mechanism underlying the antiviral phenotype of Dicer N1 expressing cells, we analyzed their transcriptome and found that many genes from the interferon and inflammatory response were upregulated. We could show that these genes appear to be controlled by transcription factors such as STAT-1, STAT-2, and NF-kB. Finally, we demonstrated that blocking the NF-kB pathway in Dicer N1 cells abrogated their antiviral phenotype. Our findings highlight the crosstalk between Dicer, PKR, and the IFN-I pathway, and suggest that human Dicer may have repurposed its helicase domain to prevent basal activation of antiviral and inflammatory pathways.

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“…Since 2013, several reports have suggested a role for antiviral RNAi in mammalian somatic but also pluripotent cells [ 28 , 29 , 34 , 35 , 36 ]. RNAi is a post-transcriptional gene-silencing mechanism orchestrated by the RNA endonuclease activity of Dicer and the slicing activity of Argonaute (Ago2 in mammals) [ 37 , 38 , 39 , 40 ].…”

Section: Alternative Antiviral Responses During Early Embryonic Devel...mentioning

confidence: 99%

“…It is, therefore, hypothesised that the IFN and RNAi responses can inhibit each other. Despite this, antiviral RNAi has been detected in non-pluripotent cell lines, including A549, HEK293T, BHK-21 and primary murine lung fibroblasts (MLFs) [ 34 , 35 ]. Supporting the cross-inhibition of RNAi and IFNs, Witteveldt et al [ 17 ] demonstrated that in the absence of the central factor for RNAi, Dicer, mESCs become capable of synthesising IFNs [ 17 ].…”

Section: Alternative Antiviral Responses During Early Embryonic Devel...mentioning

confidence: 99%

Antiviral Defence Mechanisms during Early Mammalian Development

Mueller,

Witteveldt,

Macias

2024

Viruses

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The type-I interferon (IFN) response constitutes the major innate immune pathway against viruses in mammals. Despite its critical importance for antiviral defence, this pathway is inactive during early embryonic development. There seems to be an incompatibility between the IFN response and pluripotency, the ability of embryonic cells to develop into any cell type of an adult organism. Instead, pluripotent cells employ alternative ways to defend against viruses that are typically associated with safeguard mechanisms against transposable elements. The absence of an inducible IFN response in pluripotent cells and the constitutive activation of the alternative antiviral pathways have led to the hypothesis that embryonic cells are highly resistant to viruses. However, some findings challenge this interpretation. We have performed a meta-analysis that suggests that the susceptibility of pluripotent cells to viruses is directly correlated with the presence of receptors or co-receptors for viral adhesion and entry. These results challenge the current view of pluripotent cells as intrinsically resistant to infections and raise the fundamental question of why these cells have sacrificed the major antiviral defence pathway if this renders them susceptible to viruses.

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Alphavirus infection triggers antiviral RNAi immunity in mammals

Cited by 7 publications

References 53 publications

The helicase domain of human Dicer prevents RNAi-independent activation of antiviral and inflammatory pathways

The helicase domain of human Dicer prevents RNAi-independent activation of antiviral and inflammatory pathways

Non-canonical contribution of human Dicer helicase domain in antiviral innate immune response

Antiviral Defence Mechanisms during Early Mammalian Development

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