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An upstream protein-coding region in enteroviruses modulates virus infection in gut epithelial cells.

ABSTRACT: Enteroviruses comprise a large group of mammalian pathogens that includes poliovirus. Pathology in humans ranges from sub-clinical to acute flaccid paralysis, myocarditis and meningitis. Until now, all of the enteroviral proteins were thought to derive from the proteolytic processing of a polyprotein encoded in a single open reading frame. Here we report that many enterovirus genomes also harbour an upstream open reading frame (uORF) that is subject to strong purifying selection. Using echovirus 7 and poliovirus 1, we confirmed the expression of uORF protein in infected cells. Through ribosome profiling (a technique for the global footprinting of translating ribosomes), we also demonstrated translation of the uORF in representative members of the predominant human enterovirus species, namely Enterovirus A, B and C. In differentiated human intestinal organoids, uORF protein-knockout echoviruses are attenuated compared to the wild-type at late stages of infection where membrane-associated uORF protein facilitates virus release. Thus, we have identified a previously unknown enterovirus protein that facilitates virus growth in gut epithelial cells-the site of initial viral invasion into susceptible hosts. These findings overturn the 50-year-old dogma that enteroviruses use a single-polyprotein gene expression strategy and have important implications for the understanding of enterovirus pathogenesis.

SUBMITTER: Lulla V

PROVIDER: S-EPMC6443042 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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An upstream protein-coding region in enteroviruses modulates virus infection in gut epithelial cells.

Lulla Valeria V Dinan Adam M AM Hosmillo Myra M Chaudhry Yasmin Y Sherry Lee L Irigoyen Nerea N Nayak Komal M KM Stonehouse Nicola J NJ Zilbauer Matthias M Goodfellow Ian I Firth Andrew E AE

Nature microbiology 20181126 2

Enteroviruses comprise a large group of mammalian pathogens that includes poliovirus. Pathology in humans ranges from sub-clinical to acute flaccid paralysis, myocarditis and meningitis. Until now, all of the enteroviral proteins were thought to derive from the proteolytic processing of a polyprotein encoded in a single open reading frame. Here we report that many enterovirus genomes also harbour an upstream open reading frame (uORF) that is subject to strong purifying selection. Using echovirus ...[more]

PMID: 30478287

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Project description:Anti-sense transcription originating upstream of mammalian protein-coding genes is a well-documented phenomenon, but remarkably little is known about the function or regulation of these anti-sense promoters or the non-coding RNAs they generate. Here we define at nucleotide resolution the divergent transcription start sites (TSSs) near mouse mRNAs. We find that coupled sense and anti-sense TSSs form the boundaries of an evolutionarily conserved and nucleosome-depleted regulatory region with dramatically enriched transcription factor (TF) occupancy. Notably, as the distance between sense and anti-sense TSSs increases, so does the level of TF binding and signal-dependent gene activation. We further discover a cluster of anti-sense TSSs in macrophages with an enhancer-like chromatin signature. Remarkably, this signature identifies promoters that are selectively and rapidly activated during immune challenge. We conclude that anti-sense TSSs can serve as potent, local enhancers of sense-strand gene expression by facilitating TF binding and deposition of activating histone modifications. ChIP-seq, Start-RNA-seq, and MNase-seq from mouse bone marrow-derived macrophages (BMDMs), and Start-RNA-seq from mouse embryonic fibroblasts (MEFs) are included. For ChIP-seq, two biological replicates are included for each of three treatment conditions; untreated, 30 minutes lipopolysaccharide (LPS), and 2 hours LPS. Each biological replicate for all ChIP conditions was sequenced in two lanes for depth, creating two technical replicates for each biological replicate. Raw files for paired technical replicates are labeled as repX.1 and repX.2, where repX.1 is technical replicate 1 and repX.2 is technical replicate 2. For Start-RNA-seq in BMDMs, two biological replicates are included for each of three treatment conditions; untreated, 30 min LPS, and 2 hr LPS. For MNase-seq, data from three biological replicates of untreated BMDMs are included. Four technical replicates of biological replicate 1, two technical replicates of biological replicate 2, and four technical replicates of biological replicate 3 are included. Raw files for paired technical replicates are labeled as repX.1, repX.2, repX.3, etc. For Start-RNA-seq in untreated MEFs, two biological replicates are included. Two technical replicates for each of the MEF Start-RNA-seq biological replicates are included. Paired technical replicates are labeled as repX.1 and repX.2.

Dataset Information

An upstream protein-coding region in enteroviruses modulates virus infection in gut epithelial cells.

Publications

An upstream protein-coding region in enteroviruses modulates virus infection in gut epithelial cells.

Similar Datasets

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