Noroviruses subvert the core stress granule component G3BP1 to promote viral VPg-dependent translation
- University of Cambridge, United Kingdom
- Washington University School of Medicine, United States
- Karolinska Institutet, Sweden
- University of Surrey, United Kingdom
- Yale School of Medicine, United States
Abstract
Knowledge of the host factors required for norovirus replication has been hindered by the challenges associated with culturing human noroviruses. We have combined proteomic analysis of the viral translation and replication complexes with a CRISPR screen, to identify host factors required for norovirus infection. The core stress granule component G3BP1 was identified as a host factor essential for efficient human and murine norovirus infection, demonstrating a conserved function across the Norovirus genus. Furthermore, we show that G3BP1 functions in the novel paradigm of viral VPg-dependent translation initiation, contributing to the assembly of translation complexes on the VPg-linked viral positive sense RNA genome by facilitating ribosome recruitment. Our data uncovers a novel function for G3BP1 in the life cycle of positive sense RNA viruses and identifies the first host factor with pan-norovirus pro-viral activity.
Data availability
VPg proteomics raw data, search results and FASTA files can be found as part of PRIDE submission PXD007585. Flag-virus proteomics raw data, search results and FASTA files can be found as part of PRIDE submission PXD011779.
-
VPg proteomics raw dataPRIDE PRoteomics IDEntifications, PXD007585.
-
Flag-virus proteomics raw dataPRIDE PRoteomics IDEntifications, PXD011779.
Article and author information
Author details
Marc Dominik Panas
Funding
Wellcome (207498/Z/17/Z)
- Myra Hosmillo
- Jia Lu
- James B Eaglesham
- Xinjie Wang
- Edward Emmott
- Patricia Domingues
- Yasmin Chaudhry
- Tim J Fitzmaurice
- Matthew KH Tung
- Ian G Goodfellow
National Institutes of Health (AI128043)
- Craig B Wilen
Biotechnology and Biological Sciences Research Council (BB/N001176/1)
- Jia Lu
- Ian G Goodfellow
Wellcome (104914/Z/14/Z)
- Ian G Goodfellow
Burroughs Wellcome Fund
- Craig B Wilen
Churchill College, University of Cambridge
- James B Eaglesham
Biotechnology and Biological Sciences Research Council (BB/000943N/1)
- Nicolas Locker
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Hosmillo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,494
- views
-
- 578
- downloads
-
- 55
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Noroviruses subvert the core stress granule component G3BP1 to promote viral VPg-dependent translation
eLife 8:e46681.
https://doi.org/10.7554/eLife.46681
Further reading
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Circulating sexual stages of Plasmodium falciparum (Pf) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies can efficiently block parasite transmission. In search for naturally acquired antibodies targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of Pf in the form of gametes and gametocyte extracts. We isolated mAbs reactive against a range of Pf proteins including well-established targets Pfs48/45 and Pfs230. One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition of Pf proteins, previously described only for Pf circumsporozoite protein (PfCSP), extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of the Plasmodium parasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response against Pf.
-
- Microbiology and Infectious Disease
The type VI secretion system (T6SS) is a sophisticated, contact-dependent nanomachine involved in interbacterial competition. To function effectively, the T6SS must penetrate the membranes of both attacker and target bacteria. Structures associated with the cell envelope, like polysaccharides chains, can therefore introduce spatial separation and steric hindrance, potentially affecting the efficacy of the T6SS. In this study, we examined how the capsular polysaccharide (CPS) of Acinetobacter baumannii affects T6SS’s antibacterial function. Our findings show that the CPS confers resistance against T6SS-mediated assaults from rival bacteria. Notably, under typical growth conditions, the presence of the surface-bound capsule also reduces the efficacy of the bacterium’s own T6SS. This T6SS impairment is further enhanced when CPS is overproduced due to genetic modifications or antibiotic treatment. Furthermore, we demonstrate that the bacterium adjusts the level of the T6SS inner tube protein Hcp according to its secretion capacity, by initiating a degradation process involving the ClpXP protease. Collectively, our findings contribute to a better understanding of the dynamic relationship between T6SS and CPS and how they respond swiftly to environmental challenges.
