Abstract P2187: SARS-CoV2 Nonstructural Protein, But Not The Omicron Ba.4/5 Mutant, Suppresses YAP Transcriptional Activity In The Heart

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV2, is a worldwide epidemic resulting in global healthcare crises and strained health resources. Currently, the omicron subvariants of SARS-CoV2, BA.4 and BA.5, have become the predominant variant in circulation around the world. Compared to previous variants, omicron BA.4 and BA.5 escape antibodies created by past COVID-19 vaccines and prior infections due to spike protein mutations. However, why omicron subvariants induce milder symptoms after infection are poorly understood. Here we screened SARS-CoV2 proteins and found that one nonstructural protein suppresses the transcriptional activity of YAP, the Hippo pathway signaling effector, independent of negative regulation by upstream Lats kinases in the heart. Our findings correlate with RNA sequencing data from COVID-19 patient lung samples and iPS cardiomyocytes showing decreased expression levels of YAP target genes, which suggested that SARS-CoV2 infection may affect lung epithelial cell and neonatal cardiomyocyte proliferation. Additionally, we found that the Omicron BA.4/5 variant of this viral protein suppresses YAP activity significantly less compared to the wildtype protein whose mechanism are under exploring now. These findings reveal the previously unknown function and mechanism of SARS-CoV2 nonstructural proteins in host cells. Considering the critical role of Hippo signaling in cell proliferation, apoptosis, and immune response, our data on SARS-CoV2 protein function may partially explain the lesser toxicity of Omicron BA.4/5 to the host cells.