title: Human macrophage SCN5A activates an innate immune signaling pathway for antiviral host defense.
abstract: 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.
authors.affiliation: From the Department of Neurology and Program in Cellular and Molecular Pathology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706 and.
authors.forename: Alexis
authors.initials: A
authors.lastname: Jones
authors.affiliation: From the Department of Neurology and Program in Cellular and Molecular Pathology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706 and.
authors.forename: Danielle
authors.initials: D
authors.lastname: Kainz
authors.affiliation: From the Department of Neurology and Program in Cellular and Molecular Pathology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706 and.
authors.forename: Faatima
authors.initials: F
authors.lastname: Khan
authors.affiliation: From the Department of Neurology and Program in Cellular and Molecular Pathology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706 and.
authors.forename: Cara
authors.initials: C
authors.lastname: Lee
authors.affiliation: From the Department of Neurology and Program in Cellular and Molecular Pathology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706 and the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705 carrithers@neurology.wisc.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Carrithers
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D018259:Herpesvirus 1, Human / Q000276:immunology / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011070:Poly I-C / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D034961:Antigens, Nuclear; D000998:Antiviral Agents; D001324:Autoantigens; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C066642:SP100 protein, human; D016899:Interferon-beta; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8; D011070:Poly I-C
keywords: Adenylate Cyclase; Double-stranded RNA (dsRNA); Innate Immunity; Interferon; Sodium Channel