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

Ruan et al. investigate the effect of H5N1 infection on the expression of intercellular junction proteins (E-cadherin, Occludin, Claudin-1, and ZO-1), which they find results in reduced expression of these proteins via activation of TAK1, p38, and ERK, leading to an induction of Itch. The authors report that Itch activation then results in ubiquitination and degradation of these cellular junction proteins. 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-beta-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.

Automated summary

Ruan et al. investigate the effect of H5N1 infection on the expression of intercellular junction proteins and find that it leads to reduced expression of these proteins through the activation of TAK1, p38, and ERK, resulting in the induction of Itch. The authors report that Itch activation then leads to ubiquitination and degradation of these cellular junction proteins. This study suggests that H5N1 virus infection impairs the alveolar epithelial barrier by downregulating the expression of intercellular junction proteins at the posttranslational level.