Influenza virus reduces ubiquitin E3 ligase MARCH10 expression to decrease ciliary beat frequency

Respiratory viruses, such as influenza, decrease airway cilia function and expression, which leads to reduced mucociliary clearance and inhibited overall immune defense. Ubiquitination is a posttranslational modification using E3 ligases, which plays a role in the assembly and disassembly of cilia. We examined the role of membrane-associated RING-CH (MARCH) family of E3 ligases during influenza infection and determined that MARCH10, specifically expressed in ciliated epithelial cells, is significantly decreased during influenza infection in mice, human lung epithelial cells, and human lung tissue. Cellular depletion of MARCH10 in differentiated human bronchial epithelial cells (HBECs) using CRISPR/Cas9 showed decrease in ciliary beat frequency. Furthermore, MARCH10 cellular knockdown in combination with influenza infection selec-tively decreased immunoreactive levels of the ciliary component, dynein axonemal intermediate chain 1. Cellular overex-pressi on of MARCH10 significantly decreased influenza hemagglutinin protein levels in the differentiated HBECs and knockdown of MARCH10 increased IL-1b cytokine expression, whereas overexpression had the reciprocal effect. These find-ings suggest that MARCH10 may have a protective role in airway pulmonary host defense and innate immunity during influ-enza infection.

Automated summary

Respiratory viruses, such as influenza, decrease airway cilia function and expression, which leads to reduced clearance of mucus and weakened immune defense. The study found that MARCH10, an E3 ligase expressed in ciliated epithelial cells, is significantly decreased during influenza infection in mice, human lung epithelial cells, and human lung tissue. Knockdown of MARCH10 resulted in reduced ciliary beat frequency and decreased levels of a ciliary component, while overexpression of MARCH10 decreased influenza hemagglutinin protein levels and modulated IL-1b cytokine expression. These findings suggest that MARCH10 may play a protective role in airway pulmonary host defense and innate immunity during influenza infection.