Poxviral protein E3-altered cytokine production reveals that DExD/H-box helicase 9 controls Toll-like receptor-stimulated immune responses.

Abstract

Host pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) detect viruses and other pathogens, inducing production of cytokines that cause inflammation and mobilize cells to control infection. Vaccinia virus (VACV) encodes proteins that antagonize these host innate immune responses, and elucidating the mechanisms of action of these viral proteins helped shed light on PRR signaling mechanisms. The VACV virulence factor E3 is one of the most intensely studied VACV proteins and has multiple effects on host cells, many of which cannot be explained by the currently known cellular targets of E3. Here, we report that E3 expression in human monocytes alters TLR2- and TLR8-dependent cytokine induction, and particularly inhibits interleukin (IL)-6. Using MS, we identified DExD/H-box helicase 9 (DHX9) as an E3 target. Although DHX9 has previously been implicated as a PRR for sensing nucleic acid in dendritic cells, we found no role for DHX9 as a nucleic acid-sensing PRR in monocytes. Rather, DHX9 suppression in these cells phenocopied the effects of E3 expression on TLR2- and TLR8-dependent cytokine induction, in that DHX9 was required for all TLR8-dependent cytokines measured, and for TLR2-dependent IL-6. Furthermore, DHX9 also had a cell- and stimulus-independent role in IL-6 promoter induction. DHX9 enhanced NF-κB-dependent IL-6 promoter activation, which was directly antagonized by E3. These results indicate new roles for DHX9 in regulating cytokines in innate immunity and reveal that VACV E3 disrupts innate immune responses by targeting of DHX9.

• Authors: Alan Dempsey, Sinead E Keating, Michael Carty, Andrew G Bowie
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 39 Pg. 14989-15001 (09 28 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 30111593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Dempsey et al.

Chemical References

• E3L protein, Vaccinia virus
• Interleukin-6
• Neoplasm Proteins
• RNA-Binding Proteins
• Receptors, Pattern Recognition
• TLR2 protein, human
• TLR8 protein, human
• Toll-Like Receptor 2
• Toll-Like Receptor 8
• Viral Proteins
• DHX9 protein, human
• DEAD-box RNA Helicases

Topics

• DEAD-box RNA Helicases (genetics)
• Gene Expression Regulation, Viral
• Host-Pathogen Interactions (genetics, immunology)
• Humans
• Immunity, Innate (genetics)
• Interleukin-6 (genetics)
• Monocytes (virology)
• Neoplasm Proteins (genetics)
• Promoter Regions, Genetic
• RNA-Binding Proteins (genetics)
• Receptors, Pattern Recognition (genetics)
• Toll-Like Receptor 2 (genetics)
• Toll-Like Receptor 8 (genetics)
• Vaccinia (genetics, virology)
• Vaccinia virus (genetics, pathogenicity)
• Viral Proteins (genetics)