Biology subjects

Wiebe, S.

Publications and source records attributed to Wiebe, S..

4 recordsLinked to original sources

bioRxiv2026

Epstein-Barr virus co-opts ADAR1 to evade PKR activation of the integrated stress response in nasopharyngeal carcinoma

Viruses generate immunogenic double-stranded RNA (dsRNA) during their life cycle, necessitating mechanisms to evade host innate immune detection. Protein kinase R (PKR) is a pattern recognition receptor (PRR) that senses viral dsRNA and activates the host integrated stress response (ISR) by phosphorylating eukaryotic initiation factor 2 (eIF2) on its alpha subunit, causing global mRNA translation arrest. Viruses evade activation of the ISR and translation shut-down to facilitate replication. Adenosine deaminase acting on RNA 1 (ADAR1) is uniquely positioned to support viral replication due to its ability to convert adenosine (A) into inosine (I) inside dsRNA, thereby disrupting base-pair matching and preventing PKR activation. Here, we discovered that Epstein-Barr virus (EBV), the oncogenic driver of nasopharyngeal carcinoma (NPC), requires ADAR1 both to maintain latent infection and for lytic reactivation by preventing PKR-mediated ISR activation. EBV lytic reactivation stimulated viral protein expression, which was attenuated in the absence of ADAR1. Importantly, lytic reactivation or treatment of synthetic dsRNA in the absence of ADAR1 induced phosphorylation of eIF2 by PKR, stress granule formation, and caused cancer cell lethality without the production of virion progeny. Together these findings support a strategy for EBV lytic induction therapy in NPC without viral dissemination by exposing EBV to endogenous PRRs through ADAR1 inhibition.

cancer biology↗

bioRxiv2025

4E-BP2-dependent translational control in GABAergic interneurons is required for long-term memory

mRNA translational repression by eukaryotic initiation factor 4E-binding proteins (4E-BPs), plays a critical role in synaptic plasticity and the formation of long-term memory (LTM). Among the three 4E-BP paralogs, 4E-BP2 is the predominant form expressed in neurons, and its full-body deletion in mice causes memory deficits. Mice lacking 4E-BP2 in GABAergic inhibitory interneurons, but not excitatory neurons, display autistic-like behaviors and deficits in object location and recognition. The specific mRNAs translationally regulated by 4E-BP2 in GABAergic interneurons, and how they contribute to spatial and associative memory, are unknown. Here, we show that conditional knockout (cKO) mice lacking 4E-BP2 selectively in GABAergic interneurons exhibit impairments in long-term spatial and contextual fear memory formation. We further demonstrate that 4E-BP2 deletion controls the translation of selective mRNAs in interneurons without increasing general protein synthesis. One of the mRNAs is Gal, which encodes a neuropeptide that modulates memory. Our findings provide evidence that 4E-BP2 selectively controls the translation of a subset of mRNAs in inhibitory neurons that are required for LTM formation.

neuroscience↗

bioRxiv2023

Stimulation of mRNA translation rescues hippocampal synaptic plasticity and memory in mouse models of Alzheimer's disease

Impaired synaptic plasticity and progressive memory deficits are major hallmarks of Alzheimers disease (AD). Hippocampal mRNA translation, required for memory consolidation, is defective in AD. Here, we show that systemic treatment with (2R,6R)- hydroxynorketamine (HNK), an active metabolite of the antidepressant ketamine, prevented deficits in hippocampal mRNA translation, long-term potentiation (LTP) and memory induced by AD-linked amyloid-{beta} oligomers (A{beta}Os) in mice. HNK activated hippocampal extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 (S6), which promote protein synthesis and synaptic plasticity. Stimulation of S6 phosphorylation by HNK was mTORC1-dependent, while rescue of hippocampal LTP and memory in HNK-treated A{beta}O-infused mice was ERK1/2-dependent and, partially, mTORC1- dependent. Remarkably, treatment with HNK corrected LTP and memory deficits in aged APP/PS1 mice. Transcriptomic analysis further showed that HNK rescued signaling pathways that are aberrant in APP/PS1 mice, including inflammatory and hormonal responses, and programmed cell death. Taken together, our findings demonstrate that HNK induces signaling and transcriptional responses that correct deficits in hippocampal synaptic plasticity and memory in AD mouse models. These results raise the prospect that HNK could serve as a therapeutic to prevent or reverse memory decline in AD.

neuroscience↗

bioRxiv2022

SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a novel mechanism by which the SARS-CoV-2 virus co-opts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-{beta}. We reveal that the SARS-CoV-2 encoded Non-Structural Protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-{beta} production, leading to reduced viral infection. Our findings reveal a new target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

microbiology↗