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Title: Influenza A virus facilitates its infectivity by activating p53 to inhibit the expression of interferon-induced transmembrane proteins
Authors: Wang, B.
Lam, T.H.
Soh, M.K.
Ye, Z.
Chen, J. 
Ren, E.C. 
Keywords: antinuclear antibody
beta interferon
caspase 3
caspase 7
membrane protein
nutlin 3
protein MDM2
protein p53
small interfering RNA
cell viability assay
chemiluminescence immunoassay
controlled study
CRISPR-CAS9 system
epithelium cell
gene expression
gene silencing
genetic transfection
human cell
immunofluorescence test
in vitro propagation
Influenza A virus
innate immunity
microarray analysis
protein expression
real time polymerase chain reaction
receptor down regulation
receptor upregulation
respiratory tract infection
RNA isolation
sequence analysis
transcription regulation
virus infectivity
virus replication
Western blotting
Issue Date: 2018
Publisher: Frontiers Media S.A.
Citation: Wang, B., Lam, T.H., Soh, M.K., Ye, Z., Chen, J., Ren, E.C. (2018). Influenza A virus facilitates its infectivity by activating p53 to inhibit the expression of interferon-induced transmembrane proteins. Frontiers in Immunology 9 (MAY) : 1193. ScholarBank@NUS Repository.
Abstract: Human influenza virus (IAV) are among the most common pathogens to cause human respiratory infections. A better understanding on interplay between IAV and host factors may provide clues for disease prevention and control. While many viruses are known to downregulate p53 upon entering the cell to reduce the innate host antiviral response, IAV infection is unusual in that it activates p53. However, it has not been clear whether this process has proviral or antiviral effects. In this study, using human isogenic p53 wild-type and p53null A549 cells generated from the CRISPR/Cas9 technology, we observed that p53null cells exhibit significantly reduced viral propagation when infected with influenza A virus (strain A/Puerto Rico/8/1934 H1N1). Genome-wide microarray analysis revealed that p53 regulates the expression of a large set of interferon-inducible genes, among which the interferon-induced transmembrane family members IFITM1, IFITM2, and IFITM3 were most significantly downregulated by the expression of p53. Knockdown of interferon-induced transmembrane proteins (IFITMs) by short interfering RNAs enhanced influenza virus infectivity in p53null A549 cells, while overexpressed IFITMs in A549 cells blocked virus entry. Intriguingly, regulation of IFITMs by p53 is independent of its transcriptional activity, as the p53 short isoform Δ40p53 recapitulates IFITM regulation. Taken together, these data reveal that p53 activation by IAV is an essential step in maintaining its infectivity. This novel association between human p53 and the broad spectrum antiviral proteins, the IFITMs, demonstrates a previous mechanism employed by influenza virus to enhance its propagation via p53 inhibition of IFITMs. © 2018 Wang, Lam, Soh, Ye, Chen and Ren.
Source Title: Frontiers in Immunology
ISSN: 16643224
DOI: 10.3389/fimmu.2018.01193
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