AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling.

摘要: The host protein Stimulator of Interferon Genes (STING) has been shown to be essential for recognition 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 ATP synthesis. Because controls calcium homeostasis, AMP-activated kinase (AMPK) is regulated, in part, by calcium, postulated AMPK participates STING activation; however, role yet defined. Addition an chelator or inhibitor either mouse macrophages embryonic fibroblasts (MEFs) suppressed TNF-α following stimulation with the ligand 5,6-dimethyl xanthnone-4-acetic acid (DMXAA). These pharmacological findings were corroborated showing MEFs lacking activity also failed up-regulate after treatment DMXAA natural cyclic GMP-AMP (cGAMP). As a result, AMPK-deficient exhibit impaired control vesicular stomatitis virus (VSV), sensed can cause influenza-like illness humans. This impairment could overcome pretreatment type I IFN, illustrating de novo production response VSV plays key antiviral defense during infection. Loss led dephosphorylation at Ser-555 known regulator, UNC-51-like 1 (ULK1). However, ULK1-deficient cells responded normally DMXAA, indicating promotes signaling independent ULK1 cells.