Senataxin suppresses the antiviral transcriptional response and controls viral biogenesis

• Published in: Nature immunology Vol. 16; no. 5; pp. 485 - 494
• Main Authors: Miller, Matthew S, Rialdi, Alexander, Ho, Jessica Sook Yuin, Tilove, Micah, Martinez-Gil, Luis, Moshkina, Natasha P, Peralta, Zuleyma, Noel, Justine, Melegari, Camilla, Maestre, Ana M, Mitsopoulos, Panagiotis, Madrenas, Joaquín, Heinz, Sven, Benner, Chris, Young, John A T, Feagins, Alicia R, Basler, Christopher F, Fernandez-Sesma, Ana, Becherel, Olivier J, Lavin, Martin F, van Bakel, Harm, Marazzi, Ivan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2015; Nature Publishing Group
• Subjects: 13/89; 38/61; 38/70; 42/109; 45/15; 45/43; 631/326/596; 82/81; Amyotrophic Lateral Sclerosis - genetics; Analysis; Animals; Antiviral agents; Biomedicine; Cell Line, Tumor; Cercopithecus aethiops; Cytokines - metabolism; Dogs; Down-Regulation; Genetic aspects; Health aspects; Helicases; Humans; Immune response; Immunity, Innate - genetics; Immunology; Infectious Diseases; Influenza A virus; Influenza, Human - immunology; Interferon Regulatory Factor-3 - metabolism; Madin Darby Canine Kidney Cells; Mice; Mice, Knockout; Microarray Analysis; Orthomyxoviridae; Orthomyxoviridae - physiology; Physiological aspects; RNA Helicases - genetics; RNA Helicases - metabolism; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; RNA, Small Interfering - genetics; Spinocerebellar Ataxias - congenital; Spinocerebellar Degenerations - genetics; Vector-borne diseases; Vero Cells; Virus Replication - genetics; West Nile Fever - immunology; West Nile virus; West Nile virus - physiology; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3132

Mutations in the gene encoding the helicase senataxin have well established associations with the neurodegenerative disease ALS. Marazzi et al . show that senataxin can also attenuate virus-triggered responses by controlling RNA polymerase activity at genes encoding antiviral molecules. The human helicase senataxin (SETX) has been linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS4) and ataxia with oculomotor apraxia (AOA2). Here we identified a role for SETX in controlling the antiviral response. Cells that had undergone depletion of SETX and SETX -deficient cells derived from patients with AOA2 had higher expression of antiviral mediators in response to infection than did wild-type cells. Mechanistically, we propose a model whereby SETX attenuates the activity of RNA polymerase II (RNAPII) at genes stimulated after a virus is sensed and thus controls the magnitude of the host response to pathogens and the biogenesis of various RNA viruses (e.g., influenza A virus and West Nile virus). Our data indicate a potentially causal link among inborn errors in SETX , susceptibility to infection and the development of neurologic disorders.