Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response

The Hippo signaling pathway, which is historically considered as a dominator of organ development and homeostasis has recently been implicated as an immune regulator. However, its role in host defense against influenza A virus (IAV) has not been widely investigated. Here, we found that IAV could activate the Hippo effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) through physical binding of the IAV non-structural protein 1 (NS1) with C-terminal domain of YAP/TAZ, facilitating their nuclear location. Meanwhile, YAP/TAZ downregulated the expression of pro-inflammatory and anti-viral cytokines against IAV infection, therefore benefiting virus replication and host cell apoptosis. A mouse model of IAV infection further demonstrated Yap deficiency protected mice against IAV infection, relieving lung injury. Mechanistically, YAP/TAZ blocked anti-viral innate immune signaling via downregulation of Toll-like receptor 3 (TLR3) expression. YAP directly bound to the putative TEADs binding site on the promoter region of TLR3. The elimination of acetylated histone H3 occupancy in the TLR3 promoter resulted in its transcriptional silence. Moreover, treatment of Trichostatin A, a histone deacetylases (HDACs) inhibitor or disruption of HDAC4/6 reversed the inhibition of TLR3 expression by YAP/TAZ, suggesting HDAC4/6 mediated the suppression function of YAP/TAZ. Taken together, we uncovered a novel immunomodulatory mechanism employed by IAV, where YAP/TAZ antagonize TLR3-mediated innate immunity. Author summaryThe mechanisms of influenza A virus (IAV) infection, host immune responses and interplay of host cells and virus have been under intensive study for decades of years. This has largely improved our understanding on how human immune system responses against virus and how virus evolves and develops various strategies to evade host immune surveillance. However, the panorama is far from fully elucidated, and therapeutic strategies with higher specificity of IAV are still in urgent need. In this study, we uncovered a new strategy employed by IAV to mute host innate immune response, of which NS1, a multi-functional protein of IAV activates host proteins YAP/TAZ to antagonize TLR3 expression. TLR3 mediates important innate immune signaling that produces pro-inflammatory and anti-viral cytokines against infection, thus, loss of YAP/TAZ enhances host innate immune response and protects mice from lung injuries induced by IAV infection. Our study may provide a new potential target for prevention and treatment of IAV infection.