Hepatoviruses promote very-long-chain fatty acid and sphingolipid synthesis for viral RNA replication and quasi-enveloped virus release

Sci Adv. 2023 Oct 20;9(42):eadj4198. doi: 10.1126/sciadv.adj4198. Epub 2023 Oct 20.

Abstract

Virus-induced changes in host lipid metabolism are an important but poorly understood aspect of viral pathogenesis. By combining nontargeted lipidomics analyses of infected cells and purified extracellular quasi-enveloped virions with high-throughput RNA sequencing and genetic depletion studies, we show that hepatitis A virus, an hepatotropic picornavirus, broadly manipulates the host cell lipid environment, enhancing synthesis of ceramides and other sphingolipids and transcriptionally activating acyl-coenzyme A synthetases and fatty acid elongases to import and activate long-chain fatty acids for entry into the fatty acid elongation cycle. Phospholipids with very-long-chain acyl tails (>C22) are essential for genome replication, whereas increases in sphingolipids support assembly and release of quasi-enveloped virions wrapped in membranes highly enriched for sphingomyelin and very-long-chain ceramides. Our data provide insight into how a pathogenic virus alters lipid flux in infected hepatocytes and demonstrate a distinction between lipid species required for viral RNA synthesis versus nonlytic quasi-enveloped virus release.

MeSH terms

  • Ceramides
  • Fatty Acids / metabolism
  • Hepatovirus* / metabolism
  • RNA Replication
  • RNA, Viral* / genetics
  • Sphingolipids
  • Virus Release
  • Virus Replication / physiology

Substances

  • RNA, Viral
  • Fatty Acids
  • Sphingolipids
  • Ceramides