Coronavirus hijacks STX18-ATG14 axis-regulated lipophagy to evade an anti-viral effect.

Abstract

ATG14 is a core subunit of the class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) for macroautophagy/autophagy initiation and also binds to the STX17 to promote autophagosome-lysosome fusion. Our recent work found that ATG14 also targets lipid droplets (LDs) and interacts with mammalian Atg8-family proteins (ATG8s) to mediate lipophagy (selective autophagic degradation of lipid droplets). We also demonstrated that STX18 (syntaxin 18) acts as a negative regulator that disrupts the interactions of ATG14-ATG8s and the formation of the PtdIns3K-C1 through binding to ATG14. Furthermore, we found that knockdown of STX18 induces LD-associated anti-viral protein RSAD2/Viperin degradation dependent on ATG14-mediated lipophagy. Additionally, coronavirus M protein hijacks STX18 to induce lipophagy and degrade RSAD2, facilitating virus production. In summary, our findings reveal new roles of ATG14 in lipid metabolism and viral replication as an autophagic receptor.