Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE210019 | GEO | 2022/07/31
REPOSITORIES: GEO
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Project description:Gene functional study and the emerging mRNA therapy technology heavily rely on in vitro transcribed (IVT) mRNA, but the double-stranded RNA (dsRNA) by-product generated during IVT is often recognized by cells as a marker of virus replication, leading to the integrated stress response (ISR).The biological effects of dsRNA in undifferentiated cells differ significantly from those of differentiated counterparts.Here, we found that dsRNA triggered an unprecedented ISR in zebrafish early embryos, leading to developmental delay, severe cell necrosis, and lethal malformations.Mechanistically, dsRNA stimulation caused a PKR-eIF2α independent global translation inhibition and a burst of p53 signaling. In turn, p53 activated Interferon Stimulated Genes (ISGs) and other defense-related genes in the absence of the IFN system. Unexpectedly, p53 does not promote cell death; instead, it plays a protective role in weakening the damage of translation repression by compromising protein turnover via enhanced ISGylation.This study thus unveils a distinct ISR upon dsRNA stimulation, which may help perform faithful gene overexpression in early embryos and shed light on the strategies of undifferentiated cells against RNA virus infection.
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Project description:Gene functional study and the emerging mRNA therapy technology heavily rely on in vitro transcribed (IVT) mRNA, but the double-stranded RNA (dsRNA) by-product generated during IVT is often recognized by cells as a marker of virus replication, leading to the integrated stress response (ISR).The biological effects of dsRNA in undifferentiated cells differ significantly from those of differentiated counterparts.Here, we found that dsRNA triggered an unprecedented ISR in zebrafish early embryos, leading to developmental delay, severe cell necrosis, and lethal malformations.Mechanistically, dsRNA stimulation caused a PKR-eIF2α independent global translation inhibition and a burst of p53 signaling. In turn, p53 activated Interferon Stimulated Genes (ISGs) and other defense-related genes in the absence of the IFN system. Unexpectedly, p53 does not promote cell death; instead, it plays a protective role in weakening the damage of translation repression by compromising protein turnover via enhanced ISGylation.This study thus unveils a distinct ISR upon dsRNA stimulation, which may help perform faithful gene overexpression in early embryos and shed light on the strategies of undifferentiated cells against RNA virus infection.
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