Dicer and PKR as Novel Regulators of Embryonic Stem Cell Fate and Antiviral Innate Immunity

Guo, Yan‐Lin; Gurung, Chandan; Fendereski, Mona; Huang, Faqing

doi:10.4049/jimmunol.2200042

Cited by 4 publications

(3 citation statements)

References 119 publications

(157 reference statements)

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“…Unlike differentiated cells, ESCs exhibit a much weaker response to cytoplasmic double-stranded RNA (dsRNA) and produce minimal amounts of IFN-β 93 . This reduced innate immune response might serve as a protective mechanism, allowing ESCs to avoid immune-related cytotoxicity 92 . Our results suggest that the inability to silence ERVs and repetitive elements activates an "innate immune checkpoint", leading to the elimination of cells that cannot suppress these elements during naïve-to-primed transition.…”

Section: Discussionmentioning

confidence: 99%

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TASOR expression in naive embryonic stem cells safeguards their developmental potential

Pinzon-Arteaga,

O’Hara,

Mazzagati

et al. 2024

Preprint

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The seamless transition through stages of pluripotency relies on a delicate balance between transcription factor networks and epigenetic silencing mechanisms that ensure proper regulation of the developmental program, critical for normal development. Here, we uncover the pivotal role of the transgene activation suppressor (TASOR), a component of the human silencing hub (HUSH) complex, in sustaining cell viability during the transition from naive to primed pluripotency, despite its rapid downregulation during this transition. Loss of TASOR in naive cells triggers replication stress, disrupts H3K9me3 heterochromatin formation, and compromise the transcriptional and post-transcriptional silencing of LINE-1 (L1) transposable elements (TEs), with these effects become more pronounced in primed cells. Remarkably, the survival ofTasor-knockout cells during naive to primed transition can be restored through the inhibition of cysteine-aspartic acid protease (Caspase) or deletion of mitochondrial antiviral signaling protein (MAVS). This suggests that unscheduled L1 expression activates an innate immune response, leading to programmed cell death, specifically in cells exiting naïve pluripotency. Additionally, we propose that HUSH-promoted H3K9me3 in naïve PSCs sets the stage for ensuing DNA methylation in primed cells, establishing long-term silencing during differentiation. Our findings shed insights on the crucial impact of epigenetic programs established in early developmental stages on subsequent phases, underscoring their significance in the developmental process.

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Section: Discussionmentioning

confidence: 99%

“…ESCs are immunologically different from somatic cells 92 . Unlike differentiated cells, ESCs exhibit a much weaker response to cytoplasmic double-stranded RNA (dsRNA) and produce minimal amounts of IFN-β 93 .…”

Section: Discussionmentioning

confidence: 99%

TASOR expression in naive embryonic stem cells safeguards their developmental potential

Pinzon-Arteaga,

O’Hara,

Mazzagati

et al. 2024

Preprint

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show abstract

“…Notably, using this in vitro dicing assay, they found that aviD is more resistant to LGP2 [40]. Whether other cofactors of Dicer, such as PKR‐associated activator (PACT), protein kinase RNA‐activated (PKR) and adenosine deaminases acting on RNA 1 (ADAR1), modulate the Dicer's ability to cleave dsRNA in vivo needs to be further investigated [68–70].…”

Section: Other Than Truncated Dicer Full‐length Dicer Can Also Proces...mentioning

confidence: 99%

Current advances in antiviral RNA interference in mammals

Wang

2023

The FEBS Journal

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Mammals have potent innate immune systems that work together to fight against a variety of distinct viruses. In addition to interferon (IFN) response, which has been intensively studied, antiviral RNA interference (RNAi) is gradually being studied. However, previous studies indicated low Dicer activity on double‐stranded RNA (dsRNA) substrates in vitro and that IFN response masks or inhibits antiviral RNAi in mammals. Therefore, whether or not the RNAi is functional for antiviral response in mammalian somatic cells is still an ongoing area of research. In this review, we will present the current advances in antiviral RNAi in mammals and focus on three fundamental questions critical to the intense debate about whether RNAi can function as an innate antiviral immunity in mammals.

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Mouse Trophoblast Cells Can Provide IFN-Based Antiviral Protection to Embryonic Stem Cells via Paracrine Signaling

Fendereski

Neupane

Nazneen

et al. 2022

The Journal of Immunology

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The blastocyst is the preimplantation stage embryo that consists of two major components: the inner cell mass (ICM) and the trophectoderm (TE). The ICM gives rise to the fetus and some extraembryonic tissues whereas the TE contributes to development of the placenta. Previous studies have demonstrated that both human and mouse embryonic stem cells (ESCs) derived from the ICM are deficient in expressing type I IFNs in response to viral infection. In this study, we investigated the IFN response in mouse trophoblast stem cells (TSCs) and their in vitro differentiated trophoblasts (TSC-TBs). In this study, we report that, unlike ESCs, TSCs have a functional IFN system. They can express type I IFNs in response to viral stimuli and express IFN-stimulated genes in response to type I IFNs. TSC-TBs have a further developed IFN system and acquired the ability to express specialized type III IFN-λ. Furthermore, TSCs and TSC-TBs can provide ESCs with antiviral activity against Chikungunya, West Nile, and Zika virus infection, as demonstrated with a novel coculture model that simulates the temporal and spatial relationship between the ICM and the TE in a blastocyst. Taken together, our data demonstrate that mouse ESCs can respond to type I IFNs and gain IFN-based antiviral protection from TSCs and TSC-TBs via paracrine signaling mechanisms even though they themselves are unable to express type I IFNs.

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Dicer and PKR as Novel Regulators of Embryonic Stem Cell Fate and Antiviral Innate Immunity

Cited by 4 publications

References 119 publications

TASOR expression in naive embryonic stem cells safeguards their developmental potential

TASOR expression in naive embryonic stem cells safeguards their developmental potential

Current advances in antiviral RNA interference in mammals

Mouse Trophoblast Cells Can Provide IFN-Based Antiviral Protection to Embryonic Stem Cells via Paracrine Signaling

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