Genome-wide CRISPR screens identify noncanonical translation factor eIF2A as an enhancer of SARS-CoV-2 programmed −1 ribosomal frameshifting

Summary: Many positive-strand RNA viruses, including all known coronaviruses, employ programmed −1 ribosomal frameshifting (−1 PRF) to regulate the translation of polycistronic viral RNAs. However, only a few host factors have been shown to regulate −1 PRF. Through a genome-wide CRISPR-Cas9 knockout...

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Main Authors: Lian-Huan Wei, Yu Sun, Junjie U. Guo
Format: Article
Language:English
Published: Elsevier 2023-08-01
Series:Cell Reports
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124723009981
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author Lian-Huan Wei
Yu Sun
Junjie U. Guo
author_facet Lian-Huan Wei
Yu Sun
Junjie U. Guo
author_sort Lian-Huan Wei
collection DOAJ
description Summary: Many positive-strand RNA viruses, including all known coronaviruses, employ programmed −1 ribosomal frameshifting (−1 PRF) to regulate the translation of polycistronic viral RNAs. However, only a few host factors have been shown to regulate −1 PRF. Through a genome-wide CRISPR-Cas9 knockout screen, we have identified host factors that either suppress or enhance severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) –1 PRF. Among them, eukaryotic translation initiation factor 2A (eIF2A) specifically and directly enhances −1 PRF independent of changes in initiation. Consistent with the crucial role of efficient −1 PRF in transcriptase/replicase expression, loss of eIF2A reduces SARS-CoV-2 replication in cells. Furthermore, transcriptome-wide analysis shows that eIF2A preferentially binds CG-rich RNA motifs, including a region within 18S ribosomal RNA near the contacts between the SARS-CoV-2 frameshift-stimulatory element (FSE) and the ribosome. Thus, our results indicate a role for eIF2A in modulating the translation of specific RNAs independent of its role during initiation.
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spelling doaj.art-be4479de5bc54c939a97b012aa060fa12023-08-31T05:02:26ZengElsevierCell Reports2211-12472023-08-01428112987Genome-wide CRISPR screens identify noncanonical translation factor eIF2A as an enhancer of SARS-CoV-2 programmed −1 ribosomal frameshiftingLian-Huan Wei0Yu Sun1Junjie U. Guo2Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USADepartment of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USADepartment of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Corresponding authorSummary: Many positive-strand RNA viruses, including all known coronaviruses, employ programmed −1 ribosomal frameshifting (−1 PRF) to regulate the translation of polycistronic viral RNAs. However, only a few host factors have been shown to regulate −1 PRF. Through a genome-wide CRISPR-Cas9 knockout screen, we have identified host factors that either suppress or enhance severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) –1 PRF. Among them, eukaryotic translation initiation factor 2A (eIF2A) specifically and directly enhances −1 PRF independent of changes in initiation. Consistent with the crucial role of efficient −1 PRF in transcriptase/replicase expression, loss of eIF2A reduces SARS-CoV-2 replication in cells. Furthermore, transcriptome-wide analysis shows that eIF2A preferentially binds CG-rich RNA motifs, including a region within 18S ribosomal RNA near the contacts between the SARS-CoV-2 frameshift-stimulatory element (FSE) and the ribosome. Thus, our results indicate a role for eIF2A in modulating the translation of specific RNAs independent of its role during initiation.http://www.sciencedirect.com/science/article/pii/S2211124723009981CP: Microbiology
spellingShingle Lian-Huan Wei
Yu Sun
Junjie U. Guo
Genome-wide CRISPR screens identify noncanonical translation factor eIF2A as an enhancer of SARS-CoV-2 programmed −1 ribosomal frameshifting
Cell Reports
CP: Microbiology
title Genome-wide CRISPR screens identify noncanonical translation factor eIF2A as an enhancer of SARS-CoV-2 programmed −1 ribosomal frameshifting
title_full Genome-wide CRISPR screens identify noncanonical translation factor eIF2A as an enhancer of SARS-CoV-2 programmed −1 ribosomal frameshifting
title_fullStr Genome-wide CRISPR screens identify noncanonical translation factor eIF2A as an enhancer of SARS-CoV-2 programmed −1 ribosomal frameshifting
title_full_unstemmed Genome-wide CRISPR screens identify noncanonical translation factor eIF2A as an enhancer of SARS-CoV-2 programmed −1 ribosomal frameshifting
title_short Genome-wide CRISPR screens identify noncanonical translation factor eIF2A as an enhancer of SARS-CoV-2 programmed −1 ribosomal frameshifting
title_sort genome wide crispr screens identify noncanonical translation factor eif2a as an enhancer of sars cov 2 programmed 1 ribosomal frameshifting
topic CP: Microbiology
url http://www.sciencedirect.com/science/article/pii/S2211124723009981
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