SARS-CoV-2 ORF3a positively regulates NF-?B activity by enhancing IKK?-NEMO interaction

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by SARS-CoV-2 infection. Patients with severe COVID-19 exhibit robust induction of proinflammatory cytokines, which are closely associated with the devel-opment of acute respiratory distress syndrome. However, the underlying mechanisms of the NF-kappa B activation mediated by SARS-CoV-2 infection remain poorly understood. Here, we screened SARS-CoV-2 genes and found that ORF3a induces proinflammatory cytokines by activating the NF-kappa B pathway. Moreover, we found that ORF3a interacts with IKK beta and NEMO and enhances the interaction of IKK beta-NEMO, thereby positively regulating NF-kappa B activity. Together, these results suggest ORF3a may play pivotal roles in the pathogenesis of SARS-CoV-2 and provide novel insights into the interaction between host immune responses and SARS-CoV-2 infection.