SARS-CoV-2 NSP13 suppresses the Hippo pathway downstream effector YAP

Abstract

AbstractThe Hippo pathway plays critical roles in tissue development, regeneration, and immune homeostasis. The widespread pandemic of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has resulted in a global healthcare crisis and strained health resources. How SARS-CoV-2 affects Hippo signaling in host cells has remained poorly understood. Here, we report that SARS-CoV-2 infection in patient lung cells and cardiomyocytes derived from human induced pluripotent stem cells (iPS-CMs) suppressed YAP target gene expression, as evidenced by RNA sequencing data. Furthermore, in a screening of nonstructural proteins from SARS-CoV-2, nonstructural protein 13 (NSP13) significantly inhibited YAP transcriptional activity independent of the YAP upstream suppressor kinase Lats1/2. Consistent with this, NSP13 suppressed active YAP (YAP5SA) in vivo, whereby NSP13 expression reverted the phenotype of YAP5SA transgenic mice. From a mechanistic standpoint, NSP13 helicase activity was shown to be required for its suppression of YAP. Furthermore, through the interaction of NSP13 with TEAD4, which is the most common YAP-interacting transcription factor in the nucleus, NSP13 recruited endogenous YAP suppressors such as CCT3 and TTF2 to inactivate the YAP/TEAD4 complex. These findings reveal the function and mechanism of the SARS-CoV-2 helicase NSP13 in host cells and partially explain the toxic effect of SARS-CoV-2 in particular host tissue with high YAP activity.