SARS‐CoV‐2 and Hippo Signaling Pathway: A Potential Therapeutic Target

SARS‐CoV‐2 is responsible for the ongoing COVID‐19 pandemic, which causes respiratory failure and damage to multiple organ systems. Emergence of new variants of concern (VOCs), including Omicron can potentially render the current vaccines ineffective. However, our understanding of COVID‐19 pathophysiology and molecular basis of SARS‐CoV‐2 infection is very limited. The role of the Hippo signaling pathway, an evolutionarily conserved organogenesis circuitry, in tissue inflammation and innate immune response is beginning to be understood. Given the complexity of COVID‐19 associated cell injury and immunopathogenesis processes, we investigated this Hippo pathway dynamic in SARS‐CoV‐2 infection by utilizing COVID‐19 lung samples, transcriptome and human cell models based on pluripotent stem cell‐derived cardiomyocytes (PSC‐CMs) and human primary lung air‐liquid interface (ALI) culture. The SARS‐CoV‐2 infection resulted in stoppage of cardiomyocyte beating and extensive apoptotic cell death. Especially the infection caused activation of Hippo signaling pathway in cardiomyocytes, as shown by increased level of phosphorylated form of YAP, a downstream transcriptional co‐factor involved in tissue growth, mitochondrial biogenesis and innate immunity. Similar activation was noted in SARS‐CoV‐2 infected lung ALI epithelial cells and COVID‐19 lung autopsy samples. The shRNA‐mediated partial knockdown and pharmacological inhibitor of YAP/TAZ resulted in significantly reduced SARS‐CoV‐2 replication, whereas inhibition of Hippo pathway upstream LATS1 and MST1 kinases led to enhanced virus replication. These results indicate a direct role of Hippo signaling in SARS‐CoV‐2 mediated disease pathogenesis and this pathway can be pharmacologically targeted to treat COVID‐19.