Endoplasmic reticulum-associated degradation potentiates the infectivity of influenza A virus by regulating the host redox state

Kwang Il Jung, Dong Hyun Ko, Nary Shin, Chul Woong Pyo, Sang-Yun Choi

Research output: Contribution to journalArticle

Abstract

During influenza A virus (IAV) infection, significant effects of oxidative stress often emerge due to the disruption of the redox balance. Reactive oxygen species (ROS) generated during IAV infection have been known to exert various effects on both the virus and host tissue. However, the mechanisms underlying the accumulation of ROS and their physiological significance in IAV infection have been extensively studied but remain to be fully understood. Here, we show that the levels of Sp1, a key controller of Cu-Zn superoxide dismutase (SOD1) gene expression, and SOD1 are mainly dependent upon the activity of X-box–binding protein 1 (XBP1), which is a downstream factor of the endoplasmic reticulum (ER) transmembrane sensor inositol-requiring enzyme 1 (IRE1) during ER stress. In IRE1-deficient mouse embryo fibroblasts (MEFs) or A549 human lung cells treated with XBP1 siRNA, IAV-induced Sp1 loss was mitigated. However, overexpression of the spliced form of XBP1 in IRE1-deficient MEFs resulted in a further decrease in Sp1 levels, whereas the unspliced form showed no significant differences. Treatment with proteasome inhibitor MG132 markedly inhibited the IRE1/XBP1-mediated loss of Sp1 and SOD, suggesting the involvement of proteasome-dependent ER-associated degradation (ERAD). The increase in SOD1 levels with the expression of siRNA-targeting p97, a central component of the ubiquitin–proteasome system, supports the major role of the ERAD process in IAV-mediated SOD1 loss. In addition, ROS generation due to IAV infection was attenuated in cells lacking either IRE1 or JNK. These results reveal the important roles of both IRE1/XBP1-mediated ERAD and the JNK pathway in IAV infection. Interestingly, the increase in ROS due to IAV infection is correlated with the increase in the virus titer in vitro and in vivo. However, 4-phenylbutyrate (4-PBA), an inhibitor of ER stress signaling, weakened the effect of IAV infection on SOD1 loss in a dose-dependent manner. Furthermore, the treatment of mice with 4-PBA efficiently attenuated ROS generation and ER stress in lung tissue and eventually lowered the IAV titer. These results strongly suggest that the ERAD process plays a major role in IAV infection, thus making it a potential target for antiviral drug therapy.

Original languageEnglish
Pages (from-to)293-305
Number of pages13
JournalFree Radical Biology and Medicine
Volume135
DOIs
Publication statusPublished - 2019 May 1

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Endoplasmic Reticulum-Associated Degradation
Influenza A virus
Viruses
Oxidation-Reduction
Virus Diseases
Degradation
Inositol
Reactive Oxygen Species
Endoplasmic Reticulum Stress
Enzymes
Proteins
Viral Load
Small Interfering RNA
Fibroblasts
Embryonic Structures
Lung
Proteasome Inhibitors
Tissue
MAP Kinase Signaling System
Drug therapy

Keywords

  • ER stress
  • Influenza
  • ROS
  • SOD1

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Endoplasmic reticulum-associated degradation potentiates the infectivity of influenza A virus by regulating the host redox state. / Jung, Kwang Il; Ko, Dong Hyun; Shin, Nary; Pyo, Chul Woong; Choi, Sang-Yun.

In: Free Radical Biology and Medicine, Vol. 135, 01.05.2019, p. 293-305.

Research output: Contribution to journalArticle

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