The multiple roles of nsp6 in the molecular pathogenesis of SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve and adapt after its emer-gence in late 2019. As the causative agent of the coronavirus disease 2019 (COVID-19), the replication and pathogenesis of SARS-CoV-2 have been extensively studied by the research community for vaccine and thera-peutics development. Given the importance of viral spike protein in viral infection/transmission and vaccine development, the scientific community has thus far primarily focused on studying the structure, function, and evolution of the spike protein. Other viral proteins are understudied. To fill in this knowledge gap, a few recent studies have identified nonstructural protein 6 (nsp6) as a major contributor to SARS-CoV-2 replication through the formation of replication organelles, antagonism of interferon type I (IFN-I) responses, and NLRP3 inflam-masome activation (a major factor of severe disease in COVID-19 patients). Here, we review the most recent progress on the multiple roles of nsp6 in modulating SARS-CoV-2 replication and pathogenesis.