
SARS-CoV-2感染によりホスト細胞でYAPの転写活性が抑制される。SARS-CoV-2のNSP13タンパク質がTEAD4と結合し、YAP/TEAD4複合体を不活性化することで、YAPの転写活性を抑制する。


coremsg

The Hippo pathway is critical to organ development, homeostasis, and regeneration, facilitated by 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 SARS-CoV-2 infected human lung samples and induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs), 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, inhibited YAP transcriptional activity independent of the upstream Hippo kinases LATS1/2. Consistently, introducing NSP13 into cardiomyocytes suppressed active YAP (YAP5SA) in vivo . Subsequent investigations on NSP13 mutants indicated that NSP13 helicase activity is crucial for suppressing YAP transactivation. Mechanistically, TEAD4 serves as a platform for recruiting NSP13 and YAP. NSP13 inactivates the YAP/TEAD4 transcription complex through its interacting proteins, such as transcription termination factor 2 (TTF2). These discoveries reveal a novel YAP/TEAD regulatory mechanism orchestrated by TEAD4, which provides molecular insights of Hippo-YAP regulation after SARS-CoV-2 infection.

### Competing Interest Statement

J.F.M is a founder and owns shares in Yap therapeutics. J.F.M. is a co-inventor on the following patents associated with this study: patent no. US20200206327A1 entitled Hippo pathway deficiency reverses systolic heart failure post-infarction, patent no.15/642200.PCT/US2014/069349 101191411 entitled Hippo and dystrophin complex signaling in cardiomyocyte renewal, and patent no. 15/102593.PCT/US2014/069349 9732345 entitled Hippo and dystrophin complex signaling in cardiomyocyte renewal.

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

sars-cov-2のnsp13タンパク質がhippoシグナル経路の下流エフェクターyapを抑制する


SARS-CoV-2のNSP13タンパク質がHippoシグナル経路の下流エフェクターYAPを抑制する
