Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection
Jun Xiao, Weiyun Li, Xin Zheng, Linlin Qi, Hui Wang, Chi Zhang, Xiaopeng Wan, Yuxiao Zheng, Ruiyue Zhong, Xin Zhou, Yao Lu, Zhiqi Li, Ying Qiu, Chang Liu, Fang Zhang, Yanbo Zhang, Xiaoyan Xu, Zhongzh
Journal：IMMUNITY
IF：21.52
DOI：10.1016/j.immuni.2019.11.015
PMID：
Published：2019-12-24
research field：分子生物学药理学免疫学病毒学
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.
本文使用的Yeasen产品
