The nucleocapsid (N) protein of SARS-CoV-2 was shown to bind to mannose binding lectin (MBL)-associated serine protease 2 (MASP2) (Ali YM et al. 2021; Gao T et al. 2020, medRxiv https://doi.org/10.1101/2020.03.29.20041962). The protease activity of MASP2 cleaves complement components C2 and C4 leading to the complement activation via the lectin pathway. The binding of viral N to MASP2 is thought to promote MASP2-mediated cleavage of C4 (Ali YM et al. 2021) and C2 (Kang S et al. 2021) leading to the hyperactivation of the complement system. In addition to triggering complement activation, MASP2 may promote a fibrin clot formation by cleavage of prothrombin to form activated thrombin (Krarup A et al. 2007; Bumiller-Bini V et al. 2021). Dysregulations of the complement and coagulation cascades are associated with inflammatory disorders such as thromboinflammation and correlate with COVID-19 severity (Margo C et al. 2020; Ramlall V ett al. 2020; Defendi F et al. 2021; Sinkovits G et al. 2021; Li Q & Chen Z 2021; Taoufik Y et al. 2021; Higashikuni Y et al. 2021; Bekassy Z et al. 2021). In vitro and ex vivo enzyme kinetic studies revealed that the SARS-CoV-2 N protein elevated maximal velocity (Vmax) of MASP2-catalyzed cleavage of C2 and increased Vmax:Km (Michaelis constant) ratio values, suggesting that the specificity constant (Kcat/Km) of MASP2 to substrates is increased in the presence of the viral N protein (Kang S et al. 2021). Treatment with the N protein-specific monoclonal antibody decreased Vmax of MASP2 in a dose-dependent manner (Kang S et al. 2021). Further, protein-protein docking studies and molecular dynamics simulations predicted the regions involved in the interaction between MASP2 and viral N-proteins originated from SARS-CoV-1, MERS-CoV and SARS-CoV-2 and identified possible druggable sites within the binding region of MASP2 (Flude BM et al. 2021). Monoclonal antibody that specifically targets MASP2 inhibited lectin pathway activation in vitro (Ali YM et al. 2021; Elhadad S et al. 2021) and prevented COVID-19-related endothelial cell damage, hyperinflammation and coagulation dysfunction in patients (Rambaldi A et al. 2020).

This Reactome event shows binding of SARS-CoV-2 N to human MASP2.