Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses

Publication date: Available online 10 April 2018
Source:Immunity
Author(s): Chenguang Wang, Yukun Guan, Mengze Lv, Rui Zhang, Zhaoying Guo, Xiaoming Wei, Xiaoxia Du, Jing Yang, Tong Li, Yi Wan, Xiaodong Su, Xiaojun Huang, Zhengfan Jiang
Manganese (Mn) is essential for many physiological processes, but its functions in innate immunity remain undefined. Here, we found that Mn²⁺ was required for the host defense against DNA viruses by increasing the sensitivity of the DNA sensor cGAS and its downstream adaptor protein STING. Mn²⁺ was released from membrane-enclosed organelles upon viral infection and accumulated in the cytosol where it bound directly to cGAS. Mn²⁺ enhanced the sensitivity of cGAS to double-stranded DNA (dsDNA) and its enzymatic activity, enabling cGAS to produce secondary messenger cGAMP in the presence of low concentrations of dsDNA that would otherwise be non-stimulatory. Mn²⁺ also enhanced STING activity by augmenting cGAMP-STING binding affinity. Mn-deficient mice showed diminished cytokine production and were more vulnerable to DNA viruses, and Mn-deficient STING-deficient mice showed no increased susceptibility. These findings indicate that Mn is critically involved and required for the host defense against DNA viruses.

Graphical abstract

Teaser

The cGAS-STING pathway is required for host defense against DNA viruses. Wang et al. find that upon virus infection, Manganese (Mn²⁺) is released from organelles into the cytosol and facilitates the activation of cGAS and STING. Their findings identify a role for Mn in innate immune activation and host anti-viral defense.


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