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.
Tomoyuki Shiota  1 ,  Zhucui Li  2 ,  Guan-Yuan Chen  2 ,  Kevin L McKnight  1 ,  Takayoshi Shirasaki  1 ,  Bryan Yonish  1 ,  Heyjeong Kim  3 ,  Ethan J Fritch  3 ,  Timothy P Sheahan  4 ,  Masamichi Muramatsu  5 ,  Maryna Kapustina  6 ,  Craig E Cameron  1  3 ,  You Li  1  7 ,  Qibin Zhang  2  8 ,  Stanley M Lemon  1  3  7
Affiliations
  • 1. Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 2. Center for Translational Biomedical Research, The University of North Carolina at Greensboro, Kannapolis, NC, USA.
  • 3. Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 4. Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 5. Department of Infectious Disease Research, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Hyogo, Japan.
  • 6. Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 7. Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 8. Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, NC, USA.
PMID: 37862421 DOI: 10.1126/sciadv.adj4198
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.

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