The SARS-CoV-2 nonstructural protein 15 collapses the host cytoskeleton by interacting with the host keratin type II cytoskeletal 1

COVID-19, the deadliest recorded pandemic of the 21st century, was caused by a novel coronavirus, SARS-CoV-2. To explore why this coronavirus was significantly more pathogenic than its predecessors, more information is needed about the functions of the viral proteins that contributed to this uptick in virulence. This study explored how one of these viral proteins, the nonstructural protein 15 (NSP15), interacts with the host. Our findings revealed a novel protein-protein interaction between NSP15 and the host keratin type II cytoskeletal 1 in Vero E6 cells, as determined by mass spectrometry, and subsequently validated by immunoprecipitation. We observed that when NSP15 was delivered into Vero E6 cells, the fibrous network of keratin intermediate filaments was disrupted, and the nuclear structure was lost. This disruption of the keratin cytoskeleton was then shown to cause a statistically significant reduction in cell viability of Vero E6 cells. These results indicate that the presence of NSP15 in host cells leads to a collapse of the keratin cytoskeleton. This cytoskeletal collapse could be a mechanism the virus employs to escape the infected host cell via cell lysis, once significant amounts of viral protein and progeny have accumulated.