title: AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling.
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.
authors.affiliation: From the Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland 21201.
authors.forename: Daniel
authors.initials: D
authors.lastname: Prantner
authors.affiliation: From the Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland 21201.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Perkins
authors.affiliation: From the Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland 21201 svogel@som.umaryland.edu.
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D000998:Antiviral Agents; D000071189:Autophagy-Related Protein-1 Homolog / Q000502:physiology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D007113:Immunity, Innate / Q000276:immunology*; D017737:Macrophages, Peritoneal; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D054243:Vesicular Stomatitis / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*; D000099197:STING Protein
chemical_list: D055372:AMP-Activated Protein Kinases; D000998:Antiviral Agents; D000071189:Autophagy-Related Protein-1 Homolog; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C530855:Sting1 protein, mouse; D000099197:STING Protein; C401061:Ulk2 protein, mouse; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; C112444:Ulk1 protein, mouse
keywords: AMP-activated kinase (AMPK); cytokine induction; interferon; macrophage; signal transduction