Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection

Immunity. 2020 Jan 14;52(1):109-122.e6. doi: 10.1016/j.immuni.2019.11.015. Epub 2019 Dec 24.

Abstract

Recent work suggests that cholesterol metabolism impacts innate immune responses against infection. However, the key enzymes or the natural products and mechanisms involved are not well elucidated. Here, we have shown that upon DNA and RNA viral infection, macrophages reduced 7-dehydrocholesterol reductase (DHCR7) expression. DHCR7 deficiency or treatment with the natural product 7-dehydrocholesterol (7-DHC) could specifically promote phosphorylation of IRF3 (not TBK1) and enhance type I interferon (IFN-I) production in macrophages. We further elucidated that viral infection or 7-DHC treatment enhanced AKT3 expression and activation. AKT3 directly bound and phosphorylated IRF3 at Ser385, together with TBK1-induced phosphorylation of IRF3 Ser386, to achieve IRF3 dimerization. Deletion of DHCR7 and the DHCR7 inhibitors including AY9944 and the chemotherapy drug tamoxifen promoted clearance of Zika virus and multiple viruses in vitro or in vivo. Taken together, we propose that the DHCR7 inhibitors and 7-DHC are potential therapeutics against emerging or highly pathogenic viruses.

Keywords: 7-DHC; AKT3; DHCR7; IRF3; cholesterol metabolism; infection; macrophage; type I IFN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Cell Line
  • Cholesterol / metabolism
  • Dehydrocholesterols / metabolism*
  • Enzyme Activation / immunology
  • HEK293 Cells
  • Humans
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon Type I / biosynthesis*
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors
  • Oxidoreductases Acting on CH-CH Group Donors / genetics
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • RAW 264.7 Cells
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Vesicular Stomatitis / immunology*
  • Vesicular stomatitis Indiana virus / immunology

Substances

  • Dehydrocholesterols
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Irf3 protein, mouse
  • RNA, Small Interfering
  • Cholesterol
  • 7-dehydrocholesterol
  • Oxidoreductases Acting on CH-CH Group Donors
  • 7-dehydrocholesterol reductase
  • Akt3 protein, mouse
  • Proto-Oncogene Proteins c-akt