Transcriptomic analysis of sorted lung cells revealed a proviral activity of the NF-κB pathway toward SARS-CoV-2

Bhargava, Anvita; Szachnowski, Ugo; Chazal, Maxime; Foretek, Dominika; Caval, Vincent; Aicher, Sophie-Marie; Pipoli da Fonseca, Juliana; Jeannin, Patricia; Beauclair, Guillaume; Monot, Marc; Morillon, Antonin; Jouvenet, Nolwenn

doi:10.1016/j.isci.2023.108449

Cited by 3 publications

(2 citation statements)

References 106 publications

(193 reference statements)

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“…Indeed, SARS-CoV-2 is known to benefit from the upregulation of the inflammatory response, mainly through the NF-kB pathway, which is essential for the replication and propagation of the virus (Nilsson-Payant et al, 2021 ). A very recent study confirmed the proviral role of the NF-kB pathway in SARS-CoV-2 infected lung cells (Bhargava et al, 2023 ).…”

Section: Discussionmentioning

confidence: 63%

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: Discussionmentioning

confidence: 63%

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

View full text Add to dashboard Cite

show abstract

“…Indeed, SARS-CoV-2 is known to benefit from the upregulation of the inflammatory response, mainly through the NF-kB pathway, which is essential for the replication and propagation of the virus (Nilsson-Payant et al, 2021). A very recent study confirmed the proviral role of the NF-kB pathway in SARS-CoV-2 infected lung cells (Bhargava et al, 2023).…”

Section: Discussionmentioning

confidence: 77%

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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Noncoding RNAs in the COVID-19 Saga: An Untold Story

Maqbool,

Hussain,

Shaikh

et al. 2024

Viral Immunology

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Transcriptomic analysis of sorted lung cells revealed a proviral activity of the NF-κB pathway toward SARS-CoV-2

Cited by 3 publications

References 106 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

Noncoding RNAs in the COVID-19 Saga: An Untold Story

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