DDX6 Represses Aberrant Activation of Interferon-Stimulated Genes

Abstract

SUMMARY 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 DDX6 mutant. DDX6 is distinct among DExD/H helicases that regulate the antiviral response in its singular ability to negatively regulate immunity.

Positive-sense RNA viruses reveal the complexity and dynamics of the cellular and viral epitranscriptomes during infection

“…These data also showed for the first time that DDX6 similarly modulated ZIKV gene expression. In contrast to earlier reports (94,97), we found that depletion of DDX6 did not affect levels of DENV capsid, genomic RNA or viral RNA. Although these discrepancies could be due to different viral replication efficiencies, permissiveness between different cell passages and Huh7 lines (98,99), and efficiency of siRNA knockdown, the observed decrease of m 5 Cm/m 4 4 C in all virus-infected cells clearly supports the ability of DDX6 to modulate the expression of these PTMs' biogenetic enzymes.…”

“…The most prominent of such components was the DEAD-box RNA helicase DDX6, a protein that is at the nexus of numerous RNA metabolism pathways. Furthermore, this protein can affect gene expression in different RNA viruses, including HCV and HIV-1 (56,(92)(93); is a suppressor of abnormal interferon-stimulated gene expression (94); and has been found, perhaps not coincidentally, to localize in the stress granules mentioned above (95).…”

“…It was recently shown, however, that the nuclear helicase DDX46 was capable of binding the m 6 A eraser enzyme ALKBH5 via the helicase domain, which induced demethylation of select interferon stimulated genes in response to vesicular stomatitis virus infection (96). Additionally, the ability of DDX6 to suppress anomalous expression of interferon genes supports an involvement in regulating the innate immune response of the host cell (94). Since DDX6 affects gene expression in both ZIKV and HCV, but not in DENV and PV (Figure 4, (54,56)), it is possible that DDX6 might similarly interact with writer, eraser or reader enzymes to modulate m 5 Cm/m 4 4 C modifications and expression of virus-specific interferon-stimulated genes.…”

Genetic correlations among psychiatric and immune-related phenotypes based on genome-wide association data

“…89 Similarly, a correlated locus within 22q13.1 (22:39307894-40545797, highlighted yellow in Figure 2) contains GW hits for PBC, which overlaps with voltage gated calcium channel gene CACNA1I; this gene has been implicated by both GWAS and rare-variant studies of SZ. 58,90 Another correlated locus within 11q23 (11:118579747-118743772) contained GW hits for multiple autoimmune disorders and is suspected to exert pleiotropic effects through several genes, whose functions include repression of aberrant interferon signaling (DDX6), 91 chemokine signaling between T-helper and B-cells (CXCR5), 92,93 and enzymatic break down of microbial disaccharides (TREH). 94 Notably, functional genomic studies have identified DDX6 as a gene that is perturbed during neuronal differentiation of samples derived from individuals with schizophrenia, 95 and as a peripheral blood marker of cerebrospinal fluid serotonin metabolite levels, 96 supporting its relevance to psychiatric phenotypes.…”

Biochemistry and Molecular Biology of Flaviviruses

“…233 Although DDX6 might contribute to viral replication given that it is localized close to the DENV replication site, 233 a recent report suggests that DDX6 represses activation of interferon-stimulated genes (ISGs). 416 This finding may very well explain why DENV2 replication is less efficient in DDX6 knocked down cells since reduced DDX6 primes cells to establish an antiviral state and thus could restrict DENV2 replication. The same result was observed with DENV2 and WNV infection when LSM1, another component of P bodies that also interacts with the DENV 3′UTR, was silenced.…”