Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection.
In: Immunity (10747613), Jg. 52 (2020-01-14), Heft 1, S. 109
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Zugriff:
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. • Multiple infections reduce DHCR7 expression but increase AKT3 expression in macrophages • DHCR7 deficiency and 7-DHC treatment activate the PI3K-AKT3 pathway • AKT3 binds IRF3 to enhance IRF3 Ser385 phosphorylation needed for full IRF3 activation • Targeting DHCR7 protects mice from various viral infections Cholesterol metabolism impacts innate immune responses against infection. Xiao et al. show that DHCR7 and the natural product 7-DHC regulate type I interferon production via modulate AKT3 activation. The inducible expressed AKT3 directly binds IRF3 to promote IRF3 Ser385 phosphorylation. The DHCR7 inhibitors protect against various viral infections. [ABSTRACT FROM AUTHOR]
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Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection.
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Autor/in / Beteiligte Person: | 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 |
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Zeitschrift: | Immunity (10747613), Jg. 52 (2020-01-14), Heft 1, S. 109 |
Veröffentlichung: | 2020 |
Medientyp: | academicJournal |
ISSN: | 1074-7613 (print) |
DOI: | 10.1016/j.immuni.2019.11.015 |
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