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

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...

Full description

Saved in:

Bibliographic Details
Published in:	Immunity (Cambridge, Mass.) Mass.), 2018-04, Vol.48 (4), p.675-687.e7
Main Authors:	Wang, Chenguang, Guan, Yukun, Lv, Mengze, Zhang, Rui, Guo, Zhaoying, Wei, Xiaoming, Du, Xiaoxia, Yang, Jing, Li, Tong, Wan, Yi, Su, Xiaodong, Huang, Xiaojun, Jiang, Zhengfan
Format:	Article
Language:	eng
Subjects:	Adult Animals Cell Line cGAS Computer viruses Cricetinae Cytokines Cytosol Deoxyribonucleic acid DNA DNA Virus Infections - immunology DNA viruses DNA Viruses - immunology DNA, Viral - immunology Enzymatic activity Enzyme Activation - immunology Enzymes Experiments Female Gene expression HEK293 Cells HeLa Cells Host-Pathogen Interactions Humans Immunity Immunity, Innate - immunology Infections Innate immunity interferons Low concentrations Male Manganese Manganese - metabolism Membrane Proteins - metabolism Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Nucleotidyltransferases - metabolism Organelles Propagation Sensitivity Sensitivity enhancement STING Viral infections virus infection Viruses Young Adult
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. [Display omitted] •Mn2+ is released from organelles and accumulates in the cytosol upon virus infection•Mn2+ activates anti-viral innate immunity via the cGAS-STING pathway•Mn2+ increases the sensitivity of cGAS to dsDNA and promotes STING activation•Mn-deficient mice are more vulnerable to DNA viruses 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.
ISSN:	1074-7613 1097-4180