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The astrovirus N-terminal nonstructural protein anchors replication complexes to the perinuclear ER membranes

Ali, Hashim; Noyvert, David; Hankinson, Jacqueline; Lindsey, Gemma; Lulla, Aleksei; Lulla, Valeria; (2024) The astrovirus N-terminal nonstructural protein anchors replication complexes to the perinuclear ER membranes. PLoS Pathogens , 20 (7) , Article e1011959. 10.1371/journal.ppat.1011959. Green open access

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Abstract

An essential aspect of positive-sense RNA virus replication is anchoring the replication complex (RC) to cellular membranes. Positive-sense RNA viruses employ diverse strategies, including co-translational membrane targeting through signal peptides and co-opting cellular membrane trafficking components. Often, N-terminal nonstructural proteins play a crucial role in linking the RC to membranes, facilitating the early association of the replication machinery. Astroviruses utilize a polyprotein strategy to synthesize nonstructural proteins, relying on subsequent processing to form replication-competent complexes. This study provides evidence for the perinuclear ER membrane association of RCs in five distinct human astrovirus strains. Using tagged recombinant classical human astrovirus 1 and neurotropic MLB2 strains, we establish that the N-terminal domain guides the ER membrane association. We identified di-arginine motifs responsible for the perinuclear ER retention and formation of functional RCs through mutational analysis of the N-terminal domain in replicon and reverse genetics systems. In addition, we demonstrate the association of key components of the astrovirus replication complex: double-stranded RNA, RNA-dependent RNA polymerase, protease, and N-terminal protein. Our findings highlight the intricate virus-ER interaction mechanism employed by astroviruses, potentially leading to the development of novel antiviral intervention strategies.

Type: Article
Title: The astrovirus N-terminal nonstructural protein anchors replication complexes to the perinuclear ER membranes
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.ppat.1011959
Publisher version: https://doi.org/10.1371/journal.ppat.1011959
Language: English
Additional information: © 2024 Ali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10195684
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