H5N1 infection impairs the alveolar epithelial barrier through intercellular junction proteins via Itch-mediated proteasomal degradation

Tao Ruan,Yuling Sun,Xiulong Xu,Daxin Peng,Xiufan Liu,Richard A Prinz,Jing Sun,Wei Liu,Jingting Zhang

doi:10.1038/s42003-022-03131-3

Abstract

The H5N1 subtype of the avian influenza virus causes sporadic but fatal infections in humans. H5N1 virus infection leads to the disruption of the alveolar epithelial barrier, a pathologic change that often progresses into acute respiratory distress syndrome (ARDS) and pneumonia. The mechanisms underlying this remain poorly understood. Here we report that H5N1 viruses downregulate the expression of intercellular junction proteins (E-cadherin, occludin, claudin-1, and ZO-1) in several cell lines and the lungs of H5N1 virus-infected mice. H5N1 virus infection activates TGF-β-activated kinase 1 (TAK1), which then activates p38 and ERK to induce E3 ubiquitin ligase Itch expression and to promote occludin ubiquitination and degradation. Inhibition of the TAK1-Itch pathway restores the intercellular junction structure and function in vitro and in the lungs of H5N1 virus-infected mice. Our study suggests that H5N1 virus infection impairs the alveolar epithelial barrier by downregulating the expression of intercellular junction proteins at the posttranslational level.

Highlights

The H5N1 subtype of the avian influenza virus causes sporadic but fatal infections in humans
We recently reported that H1N1 viruses activate the PI-3 and MAP kinase pathways to induce the expression of Gli[1] and Snail, two transcription factors that play an important role in down-regulating the expression of intercellular junction proteins at the transcriptional levels[32]
We recently reported that the H1N1 virus increases the paracellular permeability of the alveolar epithelium in part by activating the sonic hedgehog signaling pathway to downregulate the expression of intercellular junction proteins[32]

Summary

Introduction

The H5N1 subtype of the avian influenza virus causes sporadic but fatal infections in humans. H5N1 virus infection leads to the disruption of the alveolar epithelial barrier, a pathologic change that often progresses into acute respiratory distress syndrome (ARDS) and pneumonia. The mechanisms underlying this remain poorly understood. We report that H5N1 viruses downregulate the expression of intercellular junction proteins (E-cadherin, occludin, claudin-1, and ZO-1) in several cell lines and the lungs of H5N1 virus-infected mice. Our study suggests that H5N1 virus infection impairs the alveolar epithelial barrier by downregulating the expression of intercellular junction proteins at the posttranslational level. Claudins and occludin are the major components of the tight junction in epithelial and endothelial cells Their expression is tightly regulated at both transcriptional and posttranslational levels[7,8]. ZO-1 is ubiquitinated by interleukin-6 (IL-6)-activated Ubr-1

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