Ubiquitin E3 ligase MARCH10 targets influenza hemagglutinin for ubiquitination.

Influenza virus infection damages the airways and can cause acute lung injury. Influenza virus infection remains difficult to combat since treatment is limited to supportive care or antiviral drugs to prevent influenza early in the condition. Influenza hemagglutinin (HA) is the surface glycoprotein that facilitates viral entry by binding to sialic acid-containing receptors on the host's lung cells. Therefore, it is a promising target for the development of anti-influenza therapeutic drugs. We demonstrate that the understudied E3 ligase MARCH10 destabilizes influenza HA protein in a dose-response manner and decreases the half-life of influenza HA over time. However, it does not affect the mRNA expression of influenza HA. Further, MARCH10 specifically polyubiquitinates influenza HA targeting it for degradation. When BEAS-2B cells ectopically expressed MARCH10 and were infected with PR8 virus, 1378 genes were differentially expressed. In addition, our analysis reveals that MARCH10 upregulates multiple pathways that involved interferon signaling during influenza virus infection. These findings suggest that MARCH10 plays a protective role during influenza virus infection and may enhance airway host defense and innate immunity.