Article ; Online: AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling.
The Journal of biological chemistry
2016 Volume 292, Issue 1, Page(s) 292–304
Abstract: The host protein Stimulator of Interferon Genes (STING) has been shown to be essential ... activated protein kinase (AMPK) is regulated, in part, by intracellular calcium, we postulated that AMPK ... However, ULK1-deficient cells responded normally to DMXAA, indicating that AMPK promotes STING-dependent ...
| Abstract | The host protein Stimulator of Interferon Genes (STING) has been shown to be essential for recognition of both viral and intracellular bacterial pathogens, but its regulation remains unclear. Previously, we reported that mitochondrial membrane potential regulates STING-dependent IFN-β induction independently of ATP synthesis. Because mitochondrial membrane potential controls calcium homeostasis, and AMP-activated protein kinase (AMPK) is regulated, in part, by intracellular calcium, we postulated that AMPK participates in STING activation; however, its role has yet to be been defined. Addition of an intracellular calcium chelator or an AMPK inhibitor to either mouse macrophages or mouse embryonic fibroblasts (MEFs) suppressed IFN-β and TNF-α induction following stimulation with the STING-dependent ligand 5,6-dimethyl xanthnone-4-acetic acid (DMXAA). These pharmacological findings were corroborated by showing that MEFs lacking AMPK activity also failed to up-regulate IFN-β and TNF-α after treatment with DMXAA or the natural STING ligand cyclic GMP-AMP (cGAMP). As a result, AMPK-deficient MEFs exhibit impaired control of vesicular stomatitis virus (VSV), a virus sensed by STING that can cause an influenza-like illness in humans. This impairment could be overcome by pretreatment of AMPK-deficient MEFs with type I IFN, illustrating that de novo production of IFN-β in response to VSV plays a key role in antiviral defense during infection. Loss of AMPK also led to dephosphorylation at Ser-555 of the known STING regulator, UNC-51-like kinase 1 (ULK1). However, ULK1-deficient cells responded normally to DMXAA, indicating that AMPK promotes STING-dependent signaling independent of ULK1 in mouse cells. |
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| MeSH term(s) | AMP-Activated Protein Kinases/physiology ; Animals ; Antiviral Agents ; Autophagy-Related Protein-1 Homolog/physiology ; Cells, Cultured ; Embryo, Mammalian/cytology ; Embryo, Mammalian/immunology ; Embryo, Mammalian/metabolism ; Embryo, Mammalian/virology ; Fibroblasts/cytology ; Fibroblasts/immunology ; Fibroblasts/metabolism ; Fibroblasts/virology ; Immunity, Innate/immunology ; Macrophages, Peritoneal ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphorylation ; Protein-Serine-Threonine Kinases/physiology ; Vesicular Stomatitis/immunology ; Vesicular Stomatitis/metabolism ; Vesicular Stomatitis/virology ; Vesicular stomatitis Indiana virus/immunology | |||||
| Chemical Substances | Antiviral Agents ; Membrane Proteins ; Sting1 protein, mouse ; Ulk2 protein, mouse (EC 2.7.1.11) ; AMPK alpha1 subunit, mouse (EC 2.7.11.1) ; AMPK alpha2 subunit, mouse (EC 2.7.11.1) ; Autophagy-Related Protein-1 Homolog (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Ulk1 protein, mouse (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) | |||||
| Language | English | |||||
| Publishing date | 2016-11-22 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 2997-x | |||||
| ISSN | 1083-351X ; 0021-9258 | |||||
| ISSN (online) | 1083-351X | |||||
| ISSN | 0021-9258 | |||||
| DOI | 10.1074/jbc.M116.763268 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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