2. Academic Validation
  3. Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection

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.
Jun Xiao 1,  Weiyun Li 1,  Xin Zheng 1,  Linlin Qi 2,  Hui Wang 3,  Chi Zhang 1,  Xiaopeng Wan 4,  Yuxiao Zheng 1,  Ruiyue Zhong 1,  Xin Zhou 1,  Yao Lu 1,  Zhiqi Li 5,  Ying Qiu 1,  Chang Liu 1,  Fang Zhang 2,  Yanbo Zhang 6,  Xiaoyan Xu 7,  Zhongzhou Yang 8,  Hualan Chen 4,  Qiwei Zhai 3,  Bin Wei 9,  Hongyan Wang 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, 200031, China.
  • 2 State Key Laboratory of Virology, Wuhan Institute of Virology, Wuhan, China; School of Life Sciences, Shanghai University, Shangda Road, Shanghai, China.
  • 3 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
  • 4 State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
  • 5 Huashan Hospital, Fudan University, Shanghai, China.
  • 6 State Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, 200031, China; Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 7 State Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, 200031, China; Experimental Immunology Branch, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.
  • 8 State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
  • 9 State Key Laboratory of Virology, Wuhan Institute of Virology, Wuhan, China; School of Life Sciences, Shanghai University, Shangda Road, Shanghai, China; Cancer Center, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai 200072, China. Electronic address: [email protected].
  • 10 State Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, 200031, China; Cancer Center, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai 200072, China. Electronic address: [email protected].
PMID: 31882361 DOI: 10.1016/j.immuni.2019.11.015
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15965
    99.74%, Akt Inhibitor
    Akt