title: Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells.
abstract: The retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA-5) helicases sense viral RNA in infected cells and initiate antiviral responses such as the production of type I IFNs. Here we have shown that RIG-I and MDA-5 also initiate a proapoptotic signaling pathway that is independent of type I IFNs. In human melanoma cells, this signaling pathway required the mitochondrial adapter Cardif (also known as IPS-1) and induced the proapoptotic BH3-only proteins Puma and Noxa. RIG-I- and MDA-5-initiated apoptosis required Noxa but was independent of the tumor suppressor p53. Triggering this pathway led to efficient activation of mitochondrial apoptosis, requiring caspase-9 and Apaf-1. Surprisingly, this proapoptotic signaling pathway was also active in nonmalignant cells, but these cells were much less sensitive to apoptosis than melanoma cells. Endogenous Bcl-xL rescued nonmalignant, but not melanoma, cells from RIG-I- and MDA-5-mediated apoptosis. In addition, we confirmed the results of the in vitro studies, demonstrating that RIG-I and MDA-5 ligands both reduced human tumor lung metastasis in immunodeficient NOD/SCID mice. These results identify an IFN-independent antiviral signaling pathway initiated by RIG-I and MDA-5 that activates proapoptotic signaling and, unless blocked by Bcl-xL, results in apoptosis. Due to their immunostimulatory and proapoptotic activity, RIG-I and MDA-5 ligands have therapeutic potential due to their ability to overcome the characteristic resistance of melanoma cells to apoptosis.
authors.affiliation: Department of Dermatology and Allergology, Ludwig Maximilian University, Munich, Germany. robert.besch@med.uni-muenchen.de
authors.forename: Robert
authors.initials: R
authors.lastname: Besch
authors.forename: Hendrik
authors.initials: H
authors.lastname: Poeck
authors.forename: Tobias
authors.initials: T
authors.lastname: Hohenauer
authors.forename: Daniela
authors.initials: D
authors.lastname: Senft
authors.forename: Georg
authors.initials: G
authors.lastname: Häcker
authors.forename: Carola
authors.initials: C
authors.lastname: Berking
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruzicka
authors.forename: Simon
authors.initials: S
authors.lastname: Rothenfusser
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D053453:Caspase 9 / Q000502:physiology; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D000072640:Interferon-Induced Helicase, IFIH1; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology*; D011070:Poly I-C / Q000494:pharmacology; D011094:Polyethyleneimine / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051020:bcl-X Protein / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; D007370:Interferon Type I; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011971:Receptors, Immunologic; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D011094:Polyethyleneimine; D053453:Caspase 9; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C