SARS-CoV-2 engages replication and inflammasome activation through lipid remodeling via SREBPs

Abstract

SARS-CoV-2 and other ssRNA + viruses induce major cellular lipid rearrangements, exploiting the host's metabolic pathways to replicate. Sterol regulatory-element binding proteins (SREBPs) are a family of transcription factors that control lipid metabolism. SREBP1 is associated with the regulation of fatty acid metabolism, while SREBP2 controls cholesterol metabolism, and both isoforms are associated with lipid droplet (LD) biogenesis. SARS-CoV-2 infection has been shown to increase the expression and activation of SREBPs, but the impact of this pathway on the infection outcome is still poorly explored. Here, we evaluated the effect of pharmacologic and molecular inhibition of SREBP1 and SREBP2 in a SARS-CoV-2-infected lung epithelial cell line (Calu-3). We showed that SARS-CoV-2 infection induced the expression and activation of SREBP1 and SREBP2, enzymes of lipid metabolism and LD accumulation. Partial inhibition of SARS-CoV-2 replication and cell death was observed with the genetic knockdown of SREBP1 or SREBP2, while combined SREBP1 and SREBP2 knockdown led to synergistic inhibition. Combined SREBP1 and SREBP2 knockdown inhibited DGAT-1 expression and abrogated SARS-CoV-2-triggered LD formation in Calu-3 cells. Moreover, blockage of LD biogenesis by DGAT1 siRNA inhibited SARS-CoV-2 replication and cell death. Pharmacological inhibition with the dual SREBP activation inhibitor fatostatin reduced virus replication, cell death and LD biogenesis. In addition, we demonstrated that SARS-CoV-2 induced cell death by pyroptosis, with activation of caspase-1, cleavage of gasdermin D1 and release of IL-1β and IL-18 depending on SREBP activation. Collectively, our findings help to elucidate that SREBPs are crucial host factors required for viral replication, LD biogenesis and inflammasome activation and indicate SREBP as a host target for the development of antiviral strategies.