NSP6 of SARS-CoV-2 Dually Regulates Autophagic-Lysosomal Degradation.

The pandemic of coronavirus disease 2019 (COVID-19), brought about by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has significantly impacted public health and the economy. A fundamental aspect of addressing this virus lies in elucidating the mechanisms through which it induces disease. Our study reveals that Non-structural protein 6 (NSP6) of SARS-CoV-2 promotes the initiation of autophagy by activating Beclin1. In the later stage of autophagy, however, NSP6 causes a blockage in the autophagy-lysosome degradation via the inhibition of Mucolipin 1 (MLN1). The single nucleotide polymorphism (SNP) L37F in NSP6, which is associated with asymptomatic infection, similarly enhances the initiation of autophagy but displays a reduced ability to impede lysosome-dependent degradation. In summary, we demonstrated the dual-regulation mechanism of NSP6 in autophagy, which may be one of the reasons for targeting cellular autophagy to induce viral pathogenesis. This finding may provide promising new directions for future research and clinical interventions.