Human Macrophage SCN5A Activates an Innate Immune Signaling Pathway for Antiviral Host Defense

• Published in: The Journal of biological chemistry Vol. 289; no. 51; pp. 35326 - 35340
• Main Authors: Jones, Alexis, Kainz, Danielle, Khan, Faatima, Lee, Cara, Carrithers, Michael D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19-12-2014; American Society for Biochemistry and Molecular Biology
• Subjects: Activating Transcription Factor 2 - genetics; Activating Transcription Factor 2 - immunology; Activating Transcription Factor 2 - metabolism; Adenylate Cyclase; Adenylyl Cyclases - genetics; Adenylyl Cyclases - immunology; Adenylyl Cyclases - metabolism; Animals; Antigens, Nuclear - genetics; Antigens, Nuclear - immunology; Antigens, Nuclear - metabolism; Antiviral Agents - pharmacology; Autoantigens - genetics; Autoantigens - immunology; Autoantigens - metabolism; Blotting, Western; Cells, Cultured; Cyclic AMP - immunology; Cyclic AMP - metabolism; Double-stranded RNA (dsRNA); Gene Expression Profiling; HEK293 Cells; Herpesvirus 1, Human - immunology; Herpesvirus 1, Human - physiology; Host-Pathogen Interactions - immunology; Humans; Immunity, Innate - genetics; Immunity, Innate - immunology; Innate Immunity; Interferon; Interferon-beta - genetics; Interferon-beta - immunology; Interferon-beta - metabolism; Macrophages - immunology; Macrophages - metabolism; Macrophages - virology; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Molecular Bases of Disease; NAV1.5 Voltage-Gated Sodium Channel - genetics; NAV1.5 Voltage-Gated Sodium Channel - immunology; NAV1.5 Voltage-Gated Sodium Channel - metabolism; Oligonucleotide Array Sequence Analysis; Poly I-C - pharmacology; Protein Binding - immunology; RNA Interference; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; Sodium Channel; Adenylate Cyclase; Interferon; Sodium Channel; Double-stranded RNA (dsRNA); Innate Immunity
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.611962

Pattern recognition receptors contain a binding domain for pathogen-associated molecular patterns coupled to a signaling domain that regulates transcription of host immune response genes. Here, a novel mechanism that links pathogen recognition to channel activation and downstream signaling is proposed. We demonstrate that an intracellular sodium channel variant, human macrophage SCN5A, initiates signaling and transcription through a calcium-dependent isoform of adenylate cyclase, ADCY8, and the transcription factor, ATF2. Pharmacological stimulation with a channel agonist or treatment with cytoplasmic poly(I:C), a mimic of viral dsRNA, activates this pathway to regulate expression of SP100-related genes and interferon β. Electrophysiological analysis reveals that the SCN5A variant mediates nonselective outward currents and a small, but detectable, inward current. Intracellular poly(I:C) markedly augments an inward voltage-sensitive sodium current and inhibits the outward nonselective current. These results suggest human macrophage SCN5A initiates signaling in an innate immune pathway relevant to antiviral host defense. It is postulated that SCN5A is a novel pathogen sensor and that this pathway represents a channel activation-dependent mechanism of transcriptional regulation.
Background: Intracellular variants of voltage-gated sodium channels are expressed in macrophages.
Results: Human macrophage SCN5A regulates cAMP signaling and ATF2-mediated transcription in response to pharmacological activation or dsRNA, a pathogen-associated molecular pattern.
Conclusion: Human macrophage SCN5A acts as a pathogen sensor and mediates antiviral responses.
Significance: The SCN5A channel in human macrophages regulates a mechanism to help fight off viral infections.