DDX6 Represses Aberrant Activation of Interferon-Stimulated Genes

Publication date: 25 July 2017
Source:Cell Reports, Volume 20, Issue 4
Author(s): Jennifer H. Lumb, Qin Li, Lauren M. Popov, Siyuan Ding, Marie T. Keith, Bryan D. Merrill, Harry B. Greenberg, Jin Billy Li, Jan E. Carette
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.

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Teaser

Pathological interferon-stimulated gene (ISG) expression contributes to autoimmunity, yet the mechanisms governing ISG suppression remain obscure. Lumb et al. identify DDX6 as a potent ISG suppressor. DDX6 prevents activation of IFN-independent cell-intrinsic immunity. DDX6 works via LSM1, uncovering a potential role for the mRNA degradation machinery in ISG suppression.


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