Editors' ChoiceHost-Pathogen Interactions

Promoting cytokine production

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Sci. Signal.  09 Oct 2018:
Vol. 11, Issue 551, eaav6248
DOI: 10.1126/scisignal.aav6248

The helicase DHX9 is required for production of the cytokine IL-6 in response to Toll-like receptor stimulation.

Various pattern recognition receptors (PRRs) sense viral infections and stimulate pathways that promote the expression of genes required for an antiviral immune response, such as those encoding interferons and interleukin-6 (IL-6). Many viruses encode effector proteins that subvert this response by targeting host proteins involved in PRR signaling pathways. The Vaccinia virus (VACV) effector protein E3 is required for viral replication and pathogenesis; however not all of its targets in host cells are characterized. Dempsey et al. established a human monocytic cell line that overexpressed E3 and characterized its responses to stimulation through various Toll-like receptors (TLRs), which are part of the PRR family. The authors found that E3 suppressed the production of multiple cytokines in response to TLR8 stimulation but in particular suppressed IL-6 production in response to different TLR stimuli. Mass spectrometry analysis of VACV-infected mouse embryonic fibroblasts showed that E3 bound to DExD/H-box helicase 9 (DHX9), a well-characterized sensor of viral nucleic acids in dendritic cells. Knockdown of DHX9 in the monocytic cell line phenocopied overexpression of E3; thus, DHX9 was required for TLR8-dependent cytokine production but was also needed for IL-6 production in response to different TLR stimuli. Luciferase reporter assays indicated that DHX9 induced Il6 expression in a manner dependent on the presence of a nuclear factor κB (NF-κB) response element in the Il6 promoter. Furthermore, expression of E3 decreased TLR8-stimulated, NF-κB–dependent reporter gene induction and reduced IL-6 production, indicating that E3 could antagonize the transactivation effect of DHX9. Together, these data suggest that DHX9 promotes Il6 expression in response to various TLR stimuli but that it also might play a more receptor-proximal role in mediating TLR8 signaling, which requires further investigation.

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