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Cell Rep. 2017 Jul 25;20(4):819-831. doi: 10.1016/j.celrep.2017.06.085.

DDX6 Represses Aberrant Activation of Interferon-Stimulated Genes.

Author information

1
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
2
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
3
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Palo Alto Veterans Institute of Research, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
4
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address: carette@stanford.edu.

Abstract

The innate immune system tightly regulates activation of interferon-stimulated genes (ISGs) to avoid inappropriate expression. Pathological ISG activation resulting from aberrant nucleic acid metabolism has been implicated in autoimmune disease; however, the mechanisms governing ISG suppression are unknown. Through a genome-wide genetic screen, we identified DEAD-box helicase 6 (DDX6) as a suppressor of ISGs. Genetic ablation of DDX6 induced global upregulation of ISGs and other immune genes. ISG upregulation proved cell intrinsic, imposing an antiviral state and making cells refractory to divergent families of RNA viruses. Epistatic analysis revealed that ISG activation could not be overcome by deletion of canonical RNA sensors. However, DDX6 deficiency was suppressed by disrupting LSM1, a core component of mRNA degradation machinery, suggesting that dysregulation of RNA processing underlies ISG activation in the DDX6 mutant. DDX6 is distinct among DExD/H helicases that regulate the antiviral response in its singular ability to negatively regulate immunity.

KEYWORDS:

DDX6; DEAD-box helicase; autoimmunity; cell-intrinsic immunity; genome-scale screen; interferon; interferon-stimulated genes; viral infection

PMID:
28746868
PMCID:
PMC5551412
DOI:
10.1016/j.celrep.2017.06.085
[Indexed for MEDLINE]
Free PMC Article

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