14-3-3ζ-TRAF5 axis governs interleukin-17A signaling

Blocking IL-17A signaling is an attractive therapy in treating autoimmune diseases. Current IL-17A blockers target both signaling branches, leading to inhibition of TRAF6-based IL-6 production, and TRAF5-based CXCL-1 production. Global suppression of both branches is of concern due to the critical role IL-17A plays in the host-defense mechanisms. Our study shows that 14-3-3ζ is necessary for IL-17A-stimulated IL-6 production. We also found that 14-3-3ζ represses TRAF5-mediated suppression of IL-17A-stimulated IL-6 induction. Taken together, our results show a unique cross-talk between two branches via the 14-3-3ζ-TRAF5 axis that regulates the IL-17A signaling output. These foundational results can lead to the design of a unique inhibitor targeting a specific branch of IL-17A signaling and obtaining the desired output.