Dataset Information

Genes with 5′ terminal oligopyrimidine tracts preferentially escape global suppression of translation by the SARS-CoV-2 NSP1 protein

ABSTRACT: Viruses rely on the host translation machinery to synthesize their own proteins. Consequently, they have evolved varied mechanisms to co-opt host translation for their survival. SARS-CoV-2 relies on a non-structural protein, NSP1, for shutting down host translation. Despite this, it is currently unknown how viral proteins and host factors critical for viral replication can escape a global shutdown of host translation. Here, using a novel FACS-based assay called MeTAFlow, we report a dose-dependent reduction in both nascent protein synthesis and mRNA abundance in cells expressing NSP1. We perform RNA-Seq and matched ribosome profiling experiments to identify gene-specific changes both at the mRNA expression and translation level. We discover a functionally-coherent subset of human genes preferentially translated in the context of NSP1 expression. These genes include the translation machinery components, RNA binding proteins, and others important for viral pathogenicity. Importantly, we also uncover potential mechanisms of preferential translation through the presence of shared sites for specific RNA binding proteins and a remarkable enrichment for 5′ terminal oligo-pyrimidine tracts. Collectively, the present study suggests fine tuning of host gene expression and translation by NSP1 despite its global repressive effect on host protein synthesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158374 | GEO | 2020/10/01

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Virus infection may shut off host protein synthesis in order to achieve the replicative advantage over host cells. It is well known that human pathogenic viruses, particularly the picornaviruses, can block host protein synthesis by cleavage or inhibition of eukaryotic initiation factors (eIFs). In this study we found a novel mechanism that microRNA (miRNA) is involved in viral pathogenesis. Infection of enteroviruses can disturb the expression of host miRNAs, in which miR-141 is up-regulated and inhibits host protein synthesis by post-transcriptional repression of the target gene eIF4E, a key element for cap-dependent translation of host proteins. Knockdown of miR-141 by a specific siRNA, antagomiR-141, could restore host eIF4E expression, delay the occurrence of cytopathic effect (CPE), and impair virus propagation. We demonstrated that EV71 infection could increase early growth response 1 (EGR1) expression which induced miR-141 causing the eIF4E suppression; while silencing of EGR1 attenuated virus production. Our results suggest that enterovirus infection causes the EGR1-mediated upregulation of host miR-141, further lead to the translational switch from cap-dependent to cap-independent protein synthesis in the host cells, an environmental beneficial for viral propagation. This novel mechanism may highlight a new approach for future development of antiviral therapy. Enteroviruses in the Picornaviridae family are important human pathogens which can cause fatal diseases, including cardiopulmonary failure, aseptic meningitis, paralysis, myocarditis, and encephalomyelitis. Virus infection may induce shutoff of host protein synthesis, particularly in picornavirus, whose protein translation is cap-independent. It is known that poliovirus 2A protease cleaves eIF4G, a scaffold component of mammalian cell translational complex, leading to the shut down of host protein synthesis. Nevertheless, the cleavage of eIF4G may not be sufficient for the complete shutoff of host protein synthesis. Previous studies showed that cleavage of polyA-binding protein (PABP) by viral protease 3C and dephosphorylation of the translational repressor, eIF4E binding protein 1 (4E-BP1), also contribute to this process. The cap-binding protein, eIF4E, is the most crucial factor in determining whether cap-dependent or -independent translation takes place. The mechanism by which viral infection modulates host cell protein synthesis through interfering eIF4E expression is not yet known. miRNAs are a newly discovered class of small non-protein-coding RNAs that may act via endogenous RNA interference. Our understanding of its role in the dynamic interplay between virus and host components is quite limited. Since both virus infection and miRNAs could hinder cellular protein synthesis, whether miRNAs are involved during virus infection in shutting off host protein synthesis is still unknown. To address this issue, we analyze the altered gene and microRNA expression after EV71 infection. ***This submission represents the mRNA expression component of the study only***

Dataset Information

Genes with 5′ terminal oligopyrimidine tracts preferentially escape global suppression of translation by the SARS-CoV-2 NSP1 protein

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure