Type III interferon disrupts tissue repair of human bronchial epithelial cells via JAK-dependent activation of the Hippo pathway 3156

Abstract Description The airway epithelium coordinates antiviral defense during acute viral infection and repairs damaged tissue after infection, but how these functions are regulated is unclear. Here, we studied the effects of Type III interferon (IFNλ), a cytokine secreted by epithelial cells during the innate antiviral response, on wound healing in human bronchial epithelial cells using a scratch assay and investigated the effect of IFN signaling on LATS1/2 and YAP, key proteins in the Hippo pathway. We found that a standardized wound healed in 24 hours, but IFNλ1-treated monolayers healed to only 50% of the initial wound area in 36 hours. Using trajectory analysis, we found that IFNλ1-treated cells traveled only 75% as far as control cells during wound healing. Mechanistically, we determined that IFNλ1 triggered LATS1 phosphorylation at Ser909 (associated with kinase activity), YAP phosphorylation and degradation, and a decrease in YAP target gene expression. Using siRNA, we found that LATS1/2 knockdown rescued the effect of IFNλ1 on YAP target gene expression and wound healing. Inhibitor experiments also showed that IFNλ1 induced LATS1 phosphorylation via JAK activity, and ISG induction was not necessary for IFNλ1 to inhibit wound healing. These results show that IFNλ1 activates the Hippo pathway during viral infection to limit tissue repair, allowing for the airway epithelium to regulate the transition from a robust antiviral response to clear an infection to post-infection tissue repair. Funding Sources Supported by the Rita Allen Foundation, Fast Grants for COVID-19, Yale Fellowship in the Sciences & Engineering, Timothy Dwight Richter Fellowship, and the Rosenfeld Science Scholars Program. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)