TRIF-TAK1 signaling suppresses caspase-8/3-mediated GSDMD/E activation and pyroptosis in influenza A virus-infected airway epithelial cells
Yuling Sun, Huidi Yu, Zhihao Zhan, Wei Liu, Penggang Liu, Jing Sun, Pinghu Zhang, Xiaoquan Wang, Xiufan Liu, Xiulong Xu
Abstract
Pyroptosis plays an important role in attracting innate immune cells to eliminate infected niches. Our study focuses on how influenza A virus (IAV) infection triggers pyroptosis in respiratory epithelial cells. Here, we report that IAV infection induces pyroptosis in a human and murine airway epithelial cell line. Mechanistically, IAV infection activates caspase-8 and caspase-3, which cleave and activate gasdermin (GSDM) D and GSDME, respectively. Z-nucleic acid-binding protein 1 (ZBP1) and receptor-interacting protein kinase (RIPK) 1 activity but not RIPK3 are required for caspase-8/3 and GSDMD/E activation and pyroptosis. GSDMD/E, ZBP1, and RIPK1 knockout all block IAV-induced pyroptosis but enhance virus replication. Transforming growth factor β-activated kinase 1 (TAK1) activation via the adaptor protein TRIF suppresses RIPK1, caspase-8/3, and GSDMD/E activation and pyroptosis. The TAK1 inhibitor 5Z-oxzeneonal (5Z) enhances IAV-induced caspase-8/3 and GSDMD/E cleavage in the lung tissues of IAV-infected mice. Our study unveils a previously unrecognized mechanism of regulation of IAV-induced pyroptosis in respiratory epithelial cells.