FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication

Cell Chem Biol. 2022 May 19;29(5):799-810.e4. doi: 10.1016/j.chembiol.2021.07.022. Epub 2021 Sep 13.

Abstract

The metabolic oxidative degradation of cellular lipids severely restricts replication of hepatitis C virus (HCV), a leading cause of chronic liver disease, but little is known about the factors regulating this process in infected cells. Here we show that HCV is restricted by an iron-dependent mechanism resembling the one triggering ferroptosis, an iron-dependent form of non-apoptotic cell death, and mediated by the non-canonical desaturation of oleate to Mead acid and other highly unsaturated fatty acids by fatty acid desaturase 2 (FADS2). Genetic depletion and ectopic expression experiments show FADS2 is a key determinant of cellular sensitivity to ferroptosis. Inhibiting FADS2 markedly enhances HCV replication, whereas the ferroptosis-inducing compound erastin alters conformation of the HCV replicase and sensitizes it to direct-acting antiviral agents targeting the viral protease. Our results identify FADS2 as a rate-limiting factor in ferroptosis, and suggest the possibility of pharmacologically manipulating the ferroptosis pathway to attenuate viral replication.

Keywords: FADS2; Mead acid; direct-acting antivirals; ferroptosis; hepatitis C virus; lipid peroxidation; polyunsaturated fatty acid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • Fatty Acid Desaturases / genetics
  • Fatty Acid Desaturases / metabolism
  • Fatty Acids, Unsaturated / metabolism
  • Fatty Acids, Unsaturated / pharmacology
  • Ferroptosis*
  • Hepacivirus / metabolism
  • Hepatitis C, Chronic*
  • Humans
  • Iron
  • Permissiveness
  • Virus Replication

Substances

  • Antiviral Agents
  • Fatty Acids, Unsaturated
  • Iron
  • Fatty Acid Desaturases
  • FADS2 protein, human