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
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靶向 7-脱氢胆固醇还原酶整合胆固醇代谢和 IRF3 激活以消除感染
DOI：
10.1016/j.immuni.2019.11.015
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发表时间：
2020
期刊：
影响因子：
32.4
通讯作者：
Wang Hongyan
中科院分区：
文献类型：
--
作者：
Xiao Jun;Li Weiyun;Zheng Xin;Qi Linlin;Wang Hui;Zhang Chi;Wan Xiaopeng;Zheng Yuxiao;Zhong Ruiyue;Zhou Xin;Lu Yao;Li Zhiqi;Qiu Ying;Liu Chang;Zhang Fang;Zhang Yanbo;Xu Xiaoyan;Yang Zhongzhou;Chen Hualan;Zhai Qiwei;Wei Bin;Wang Hongyan
最近的研究表明，胆固醇代谢影响先天性免疫反应对感染。然而，涉及的关键酶或天然产物和机制还没有很好地阐明。在这里，我们已经表明，在DNA和RNA病毒感染，巨噬细胞减少7-脱氢胆固醇还原酶（DHCR 7）的表达。DHCR 7缺乏或用天然产物7-脱氢胆固醇（7-DHC）治疗可以特异性促进IRF 3（而不是TBK 1）的磷酸化并增强巨噬细胞中I型干扰素（IFN-I）的产生。我们进一步阐明了病毒感染或7-DHC处理增强了AKT 3的表达和活化。AKT 3在Ser 385处直接结合并磷酸化IRF 3，连同TBK 1诱导的IRF 3 Ser 386磷酸化，以实现IRF 3二聚化。缺失DHCR 7和DHCR 7抑制剂（包括AY 9944和化疗药物他莫昔芬）可促进寨卡病毒和多种病毒在体外或体内的清除。综上所述，我们提出DHCR 7抑制剂和7-DHC是针对新出现的或高致病性病毒的潜在治疗剂。
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 virusesin vitroorin vivo. Taken together, we propose that the DHCR7 inhibitors and 7-DHC are potential therapeutics against emerging or highly pathogenic viruses.