Respiratory Syncytial Virus Matrix Protein-Chromatin Association Is Key to Transcriptional Inhibition in Infected Cells

Hong-Mei Li; Reena Ghildyal; Mengjie Hu; Kim C. Tran; Lora M. Starrs; John Mills; Michael N. Teng; David A. Jans

doi:10.3390/cells10102786

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Respiratory Syncytial Virus Matrix Protein-Chromatin Association Is Key to Transcriptional Inhibition in Infected Cells

Journal article

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Respiratory Syncytial Virus Matrix Protein-Chromatin Association Is Key to Transcriptional Inhibition in Infected Cells

Hong-Mei Li, Reena Ghildyal, Mengjie Hu, Kim C. Tran, Lora M. Starrs, John Mills, Michael N. Teng and David A. Jans

Cells (Basel, Switzerland), Vol.10(10), pp.1-21

18/10/2021

DOI: https://doi.org/10.3390/cells10102786

PMID: 34685766

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Abstract

Cell Biology

Life Sciences & Biomedicine

Science & Technology

respiratory syncytial virus (RSV)

RSV M protein

transcription inhibition

reverse genetics

nucleotide binding domain

The morbidity and mortality caused by the globally prevalent human respiratory pathogen respiratory syncytial virus (RSV) approaches that world-wide of influenza. We previously demonstrated that the RSV matrix (M) protein shuttles, in signal-dependent fashion, between host cell nucleus and cytoplasm, and that this trafficking is central to RSV replication and assembly. Here we analyse in detail the nuclear role of M for the first time using a range of novel approaches, including quantitative analysis of de novo cell transcription in situ in the presence or absence of RSV infection or M ectopic expression, as well as in situ DNA binding. We show that M, dependent on amino acids 110–183, inhibits host cell transcription in RSV-infected cells as well as cells transfected to express M, with a clear correlation between nuclear levels of M and the degree of transcriptional inhibition. Analysis of bacterially expressed M protein and derivatives thereof mutated in key residues within M’s RNA binding domain indicates that M can bind to DNA as well as RNA in a cell-free system. Parallel results for point-mutated M derivatives implicate arginine 170 and lysine 172, in contrast to other basic residues such as lysine 121 and 130, as critically important residues for inhibition of transcription and DNA binding both in situ and in vitro. Importantly, recombinant RSV carrying arginine 170/lysine 172 mutations shows attenuated infectivity in cultured cells and in an animal model, concomitant with altered inflammatory responses. These findings define an RSV M-chromatin interface critical for host transcriptional inhibition in infection, with important implications for anti-RSV therapeutic development.

Details

Title: Respiratory Syncytial Virus Matrix Protein-Chromatin Association Is Key to Transcriptional Inhibition in Infected Cells
Creators: Hong-Mei Li - Monash University
Reena Ghildyal - University of Canberra
Mengjie Hu - Monash University
Kim C. Tran - University of South Florida
Lora M. Starrs - University of Canberra
John Mills - Burnet Institute
Michael N. Teng - University of South Florida
David A. Jans - Monash University
Publication Details: Cells (Basel, Switzerland), Vol.10(10), pp.1-21
Publisher: MDPI
Number of pages: 21
Grant note: APP1043511; APP1002486/1103050 / National Health and Medical Research Council (Australia); National Health and Medical Research Council of Australia
Identifiers: 991013035749802368
Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Academic Unit: National Centre for Naturopathic Medicine
Language: English
Resource Type: Journal article

Respiratory Syncytial Virus Matrix Protein-Chromatin Association Is Key to Transcriptional Inhibition in Infected Cells

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