Tsai MuChun, Koch Dan, Forchione Anna, Farkas Laszlo, El-Mergawy Rabab, Londino James D, Mallampalli Rama K
Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine Division, The Ohio State University, Columbus, OH, USA.
Department of Internal Medicine, Pulmonary, Critical Care and Sleep Medicine Division, The Ohio State University, Columbus, OH, USA.
Cell Signal. 2025 Jul 30;135:112035. doi: 10.1016/j.cellsig.2025.112035.
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.
流感病毒感染会损害气道并可导致急性肺损伤。由于治疗仅限于支持性护理或在疾病早期预防流感的抗病毒药物，流感病毒感染仍然难以对抗。流感血凝素（HA）是一种表面糖蛋白，通过与宿主肺细胞上含唾液酸的受体结合促进病毒进入。因此，它是开发抗流感治疗药物的一个有前景的靶点。我们证明，研究较少的E3连接酶MARCH10以剂量反应方式使流感HA蛋白不稳定，并随着时间的推移降低流感HA的半衰期。然而，它不影响流感HA的mRNA表达。此外，MARCH10特异性地将流感HA多聚泛素化，使其靶向降解。当BEAS-2B细胞异位表达MARCH10并感染PR8病毒时，有1378个基因差异表达。此外，我们的分析表明，MARCH10在流感病毒感染期间上调了多个涉及干扰素信号传导的途径。这些发现表明，MARCH10在流感病毒感染期间发挥保护作用，并可能增强气道宿主防御和先天免疫。
