Influenza a virus-induced expression of a galnac transferase, GALNT3, via micrornas is required for enhanced viral replication

Shoko Nakamura, Masayuki Horie, Tomo Daidoji, Tomoyuki Honda, Mayo Yasugi, Atsushi Kuno, Toshihisa Komori, Daisuke Okuzaki, Hisashi Narimatsu, Takaaki Nakaya, Keizo Tomonaga

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Influenza A virus (IAV) affects the upper and lower respiratory tracts and rapidly induces the expression of mucins, which are common O-glycosylated proteins, on the epithelial surfaces of the respiratory tract. Although mucin production is associated with the inhibition of virus transmission as well as characteristic clinical symptoms, little is known regarding how mucins are produced on the surfaces of respiratory epithelial cells and how they affect IAV replication. In this study, we found that two microRNAs (miRNAs), miR-17-3p and miR-221, which target GalNAc transferase 3 (GALNT3) mRNA, are rapidly downregulated in human alveolar basal epithelial cells during the early stage of IAV infection.Wedemonstrated that the expression of GALNT3mRNAis upregulated in an IAV replication-dependent fashion and leads to mucin production in bronchial epithelial cells. A lectin microarray analysis revealed that the stable expression of GALNT3 by human alveolar basal epithelial cells induces mucin-type O-glycosylation modifications similar to those present in IAV-infected cells, suggesting that GALNT3 promotes mucin-type O-linked glycosylation in IAV-infected cells. Notably, analyses using short interfering RNAs and miRNA mimics showed that GALNT3 knockdown significantly reduces IAV replication. Furthermore, IAV replication was markedly decreased in embryonic fibroblast cells obtained from galnt3-knockout mice. Interestingly, IAV-infected galnt3-knockout mice exhibited high mortality and severe pathological alterations in the lungs compared to those of wild-type mice. Our results demonstrate not only the molecular mechanism underlying rapid mucin production during IAV infection but also the contribution of O-linked glycosylation to the replication and propagation of IAV in lung cells.

Original languageEnglish (US)
Pages (from-to)1788-1801
Number of pages14
JournalJournal of Virology
Volume90
Issue number4
DOIs
StatePublished - 2016
Externally publishedYes

Fingerprint

Influenza A virus
Orthomyxoviridae
virus replication
MicroRNAs
microRNA
transferases
mucins
Mucins
Virus Replication
epithelial cells
glycosylation
Glycosylation
Alveolar Epithelial Cells
Virus Diseases
respiratory system
Knockout Mice
Respiratory System
Mucin-3
mice
polypeptide N-acetylgalactosaminyltransferase

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Influenza a virus-induced expression of a galnac transferase, GALNT3, via micrornas is required for enhanced viral replication. / Nakamura, Shoko; Horie, Masayuki; Daidoji, Tomo; Honda, Tomoyuki; Yasugi, Mayo; Kuno, Atsushi; Komori, Toshihisa; Okuzaki, Daisuke; Narimatsu, Hisashi; Nakaya, Takaaki; Tomonaga, Keizo.

In: Journal of Virology, Vol. 90, No. 4, 2016, p. 1788-1801.

Research output: Contribution to journalArticle

Nakamura, S, Horie, M, Daidoji, T, Honda, T, Yasugi, M, Kuno, A, Komori, T, Okuzaki, D, Narimatsu, H, Nakaya, T & Tomonaga, K 2016, 'Influenza a virus-induced expression of a galnac transferase, GALNT3, via micrornas is required for enhanced viral replication', Journal of Virology, vol. 90, no. 4, pp. 1788-1801. https://doi.org/10.1128/JVI.02246-15
Nakamura, Shoko ; Horie, Masayuki ; Daidoji, Tomo ; Honda, Tomoyuki ; Yasugi, Mayo ; Kuno, Atsushi ; Komori, Toshihisa ; Okuzaki, Daisuke ; Narimatsu, Hisashi ; Nakaya, Takaaki ; Tomonaga, Keizo. / Influenza a virus-induced expression of a galnac transferase, GALNT3, via micrornas is required for enhanced viral replication. In: Journal of Virology. 2016 ; Vol. 90, No. 4. pp. 1788-1801.
@article{ba73d38961ef4138b0004899adbd3b7a,
title = "Influenza a virus-induced expression of a galnac transferase, GALNT3, via micrornas is required for enhanced viral replication",
abstract = "Influenza A virus (IAV) affects the upper and lower respiratory tracts and rapidly induces the expression of mucins, which are common O-glycosylated proteins, on the epithelial surfaces of the respiratory tract. Although mucin production is associated with the inhibition of virus transmission as well as characteristic clinical symptoms, little is known regarding how mucins are produced on the surfaces of respiratory epithelial cells and how they affect IAV replication. In this study, we found that two microRNAs (miRNAs), miR-17-3p and miR-221, which target GalNAc transferase 3 (GALNT3) mRNA, are rapidly downregulated in human alveolar basal epithelial cells during the early stage of IAV infection.Wedemonstrated that the expression of GALNT3mRNAis upregulated in an IAV replication-dependent fashion and leads to mucin production in bronchial epithelial cells. A lectin microarray analysis revealed that the stable expression of GALNT3 by human alveolar basal epithelial cells induces mucin-type O-glycosylation modifications similar to those present in IAV-infected cells, suggesting that GALNT3 promotes mucin-type O-linked glycosylation in IAV-infected cells. Notably, analyses using short interfering RNAs and miRNA mimics showed that GALNT3 knockdown significantly reduces IAV replication. Furthermore, IAV replication was markedly decreased in embryonic fibroblast cells obtained from galnt3-knockout mice. Interestingly, IAV-infected galnt3-knockout mice exhibited high mortality and severe pathological alterations in the lungs compared to those of wild-type mice. Our results demonstrate not only the molecular mechanism underlying rapid mucin production during IAV infection but also the contribution of O-linked glycosylation to the replication and propagation of IAV in lung cells.",
author = "Shoko Nakamura and Masayuki Horie and Tomo Daidoji and Tomoyuki Honda and Mayo Yasugi and Atsushi Kuno and Toshihisa Komori and Daisuke Okuzaki and Hisashi Narimatsu and Takaaki Nakaya and Keizo Tomonaga",
year = "2016",
doi = "10.1128/JVI.02246-15",
language = "English (US)",
volume = "90",
pages = "1788--1801",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "4",

}

TY - JOUR

T1 - Influenza a virus-induced expression of a galnac transferase, GALNT3, via micrornas is required for enhanced viral replication

AU - Nakamura, Shoko

AU - Horie, Masayuki

AU - Daidoji, Tomo

AU - Honda, Tomoyuki

AU - Yasugi, Mayo

AU - Kuno, Atsushi

AU - Komori, Toshihisa

AU - Okuzaki, Daisuke

AU - Narimatsu, Hisashi

AU - Nakaya, Takaaki

AU - Tomonaga, Keizo

PY - 2016

Y1 - 2016

N2 - Influenza A virus (IAV) affects the upper and lower respiratory tracts and rapidly induces the expression of mucins, which are common O-glycosylated proteins, on the epithelial surfaces of the respiratory tract. Although mucin production is associated with the inhibition of virus transmission as well as characteristic clinical symptoms, little is known regarding how mucins are produced on the surfaces of respiratory epithelial cells and how they affect IAV replication. In this study, we found that two microRNAs (miRNAs), miR-17-3p and miR-221, which target GalNAc transferase 3 (GALNT3) mRNA, are rapidly downregulated in human alveolar basal epithelial cells during the early stage of IAV infection.Wedemonstrated that the expression of GALNT3mRNAis upregulated in an IAV replication-dependent fashion and leads to mucin production in bronchial epithelial cells. A lectin microarray analysis revealed that the stable expression of GALNT3 by human alveolar basal epithelial cells induces mucin-type O-glycosylation modifications similar to those present in IAV-infected cells, suggesting that GALNT3 promotes mucin-type O-linked glycosylation in IAV-infected cells. Notably, analyses using short interfering RNAs and miRNA mimics showed that GALNT3 knockdown significantly reduces IAV replication. Furthermore, IAV replication was markedly decreased in embryonic fibroblast cells obtained from galnt3-knockout mice. Interestingly, IAV-infected galnt3-knockout mice exhibited high mortality and severe pathological alterations in the lungs compared to those of wild-type mice. Our results demonstrate not only the molecular mechanism underlying rapid mucin production during IAV infection but also the contribution of O-linked glycosylation to the replication and propagation of IAV in lung cells.

AB - Influenza A virus (IAV) affects the upper and lower respiratory tracts and rapidly induces the expression of mucins, which are common O-glycosylated proteins, on the epithelial surfaces of the respiratory tract. Although mucin production is associated with the inhibition of virus transmission as well as characteristic clinical symptoms, little is known regarding how mucins are produced on the surfaces of respiratory epithelial cells and how they affect IAV replication. In this study, we found that two microRNAs (miRNAs), miR-17-3p and miR-221, which target GalNAc transferase 3 (GALNT3) mRNA, are rapidly downregulated in human alveolar basal epithelial cells during the early stage of IAV infection.Wedemonstrated that the expression of GALNT3mRNAis upregulated in an IAV replication-dependent fashion and leads to mucin production in bronchial epithelial cells. A lectin microarray analysis revealed that the stable expression of GALNT3 by human alveolar basal epithelial cells induces mucin-type O-glycosylation modifications similar to those present in IAV-infected cells, suggesting that GALNT3 promotes mucin-type O-linked glycosylation in IAV-infected cells. Notably, analyses using short interfering RNAs and miRNA mimics showed that GALNT3 knockdown significantly reduces IAV replication. Furthermore, IAV replication was markedly decreased in embryonic fibroblast cells obtained from galnt3-knockout mice. Interestingly, IAV-infected galnt3-knockout mice exhibited high mortality and severe pathological alterations in the lungs compared to those of wild-type mice. Our results demonstrate not only the molecular mechanism underlying rapid mucin production during IAV infection but also the contribution of O-linked glycosylation to the replication and propagation of IAV in lung cells.

UR - http://www.scopus.com/inward/record.url?scp=84958074687&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958074687&partnerID=8YFLogxK

U2 - 10.1128/JVI.02246-15

DO - 10.1128/JVI.02246-15

M3 - Article

VL - 90

SP - 1788

EP - 1801

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 4

ER -