SARS-CoV-2 NSP13 interacts with TEAD to suppress Hippo-YAP signaling

The Hippo pathway controls organ development, homeostasis, and regeneration primarily by modulating YAP/TEAD-mediated gene expression. Although emerging studies report Hippo-YAP dysfunction after viral infection, it is largely unknown in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we analyzed RNA sequencing data from human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and SARS-CoV-2-infected human lung samples, and observed a decrease in YAP target gene expression. In screening SARS-CoV-2 nonstructural proteins, we found that nonstructural protein 13 (NSP13), a conserved coronavirus helicase, inhibits YAP transcriptional activity independent of the upstream Hippo kinases LATS1/2. Consistently, introducing NSP13 into mouse cardiomyocytes suppresses an active form of YAP (YAP5SA) <i>in vivo</i>. Subsequent investigations on NSP13 mutants revealed that NSP13 helicase activity, including DNA binding and unwinding, is crucial for suppressing YAP transactivation in HEK293T cells. Mechanistically, TEAD4 serves as a platform to recruit NSP13 and YAP. NSP13 likely inactivates the YAP/TEAD4 transcription complex by remodeling chromatin to recruit proteins, such as transcription termination factor 2 (TTF2), to bind the YAP/TEAD/NSP13 complex. These findings reveal a novel YAP/TEAD regulatory mechanism and uncover molecular insights into Hippo-YAP regulation after SARS-CoV-2 infection in humans.