1. Senataxin suppresses the antiviral transcriptional response and controls viral biogenesis.
- Author
-
Miller MS, Rialdi A, Ho JS, Tilove M, Martinez-Gil L, Moshkina NP, Peralta Z, Noel J, Melegari C, Maestre AM, Mitsopoulos P, Madrenas J, Heinz S, Benner C, Young JA, Feagins AR, Basler CF, Fernandez-Sesma A, Becherel OJ, Lavin MF, van Bakel H, and Marazzi I
- Subjects
- Animals, Cell Line, Tumor, Chlorocebus aethiops, Cytokines metabolism, DNA Helicases, Dogs, Down-Regulation, Humans, Immunity, Innate genetics, Interferon Regulatory Factor-3 metabolism, Madin Darby Canine Kidney Cells, Mice, Mice, Knockout, Microarray Analysis, Multifunctional Enzymes, RNA Helicases genetics, RNA Polymerase II genetics, RNA, Small Interfering genetics, Spinocerebellar Ataxias congenital, Vero Cells, Virus Replication genetics, Amyotrophic Lateral Sclerosis genetics, Influenza, Human immunology, Orthomyxoviridae physiology, RNA Helicases metabolism, RNA Polymerase II metabolism, Spinocerebellar Degenerations genetics, West Nile Fever immunology, West Nile virus physiology
- Abstract
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.
- Published
- 2015
- Full Text
- View/download PDF