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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / genetics*
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Animals
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Cell Line, Tumor
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Chlorocebus aethiops
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Cytokines / metabolism
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DNA Helicases
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Dogs
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Down-Regulation
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Humans
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Immunity, Innate / genetics
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Influenza, Human / immunology*
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Interferon Regulatory Factor-3 / metabolism
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Madin Darby Canine Kidney Cells
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Mice
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Mice, Knockout
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Microarray Analysis
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Multifunctional Enzymes
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Orthomyxoviridae / physiology*
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RNA Helicases / genetics
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RNA Helicases / metabolism*
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RNA Polymerase II / genetics
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RNA Polymerase II / metabolism*
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RNA, Small Interfering / genetics
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Spinocerebellar Ataxias / congenital
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Spinocerebellar Degenerations / genetics*
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Vero Cells
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Virus Replication / genetics
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West Nile Fever / immunology*
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West Nile virus / physiology*
Substances
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Cytokines
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Multifunctional Enzymes
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RNA, Small Interfering
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RNA Polymerase II
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SETX protein, human
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DNA Helicases
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RNA Helicases
Supplementary concepts
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Spinocerebellar ataxia, autosomal recessive 1