Human macrophage SCN5A activates an innate immune signaling pathway for antiviral host defense.
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.
['Jones|Alexis|A|', 'Kainz|Danielle|D|', 'Khan|Faatima|F|', 'Lee|Cara|C|', 'Carrithers|Michael D|MD|']
D051698:Activating Transcription Factor 2 D000262:Adenylyl Cyclases D000818:Animals D034961:Antigens, Nuclear D000998:Antiviral Agents D001324:Autoantigens D015153:Blotting, Western D002478:Cells, Cultured D000242:Cyclic AMP D020869:Gene Expression Profiling D057809:HEK293 Cells D018259:Herpesvirus 1, Human D054884:Host-Pathogen Interactions D006801:Humans D007113:Immunity, Innate D016899:Interferon-beta D008264:Macrophages D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D008856:Microscopy, Fluorescence D062554:NAV1.5 Voltage-Gated Sodium Channel D020411:Oligonucleotide Array Sequence Analysis D011070:Poly I-C D011485:Protein Binding D034622:RNA Interference D015398:Signal Transduction
Innate Immunity Sodium Channel Adenylate Cyclase Interferon Double-stranded RNA (dsRNA)