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

Proc Natl Acad Sci U S A. 2020 Oct 6;117(40):25008-25017. doi: 10.1073/pnas.2008214117. Epub 2020 Sep 23.

Abstract

IL-17A is a therapeutic target in many autoimmune diseases. Most nonhematopoietic cells express IL-17A receptors and respond to extracellular IL-17A by inducing proinflammatory cytokines. The IL-17A signal transduction triggers two broad, TRAF6- and TRAF5-dependent, intracellular signaling pathways to produce representative cytokines (IL-6) and chemokines (CXCL-1), respectively. Our limited understanding of the cross-talk between these two branches has generated a crucial gap of knowledge, leading to therapeutics indiscriminately blocking IL-17A and global inhibition of its target genes. In previous work, we discovered an elevated expression of 14-3-3 proteins in inflammatory aortic disease, a rare human autoimmune disorder with increased levels of IL-17A. Here we report that 14-3-3ζ is essential for IL-17 signaling by differentially regulating the signal-induced IL-6 and CXCL-1. Using genetically manipulated human and mouse cells, and ex vivo and in vivo rat models, we uncovered a function of 14-3-3ζ. As a part of the molecular mechanism, we show that 14-3-3ζ interacts with several TRAF proteins; in particular, its interaction with TRAF5 and TRAF6 is increased in the presence of IL-17A. In contrast to TRAF6, we found TRAF5 to be an endogenous suppressor of IL-17A-induced IL-6 production, an effect countered by 14-3-3ζ. Furthermore, we observed that 14-3-3ζ interaction with TRAF proteins is required for the IL-17A-induced IL-6 levels. Together, our results show that 14-3-3ζ is an essential component of IL-17A signaling and IL-6 production, an effect that is suppressed by TRAF5. To the best of our knowledge, this report of the 14-3-3ζ-TRAF5 axis, which differentially regulates IL-17A-induced IL-6 and CXCL-1 production, is unique.

Keywords: 14-3-3ζ; IL-17A; TRAF.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / genetics
  • Animals
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / pathology
  • Chemokine CXCL1 / genetics*
  • Chemokines / genetics
  • Cytokines / genetics
  • Gene Expression Regulation / genetics
  • Humans
  • Interleukin-17 / genetics*
  • Interleukin-6 / genetics*
  • Mice
  • Rats
  • Signal Transduction / genetics
  • TNF Receptor-Associated Factor 5 / genetics
  • TNF Receptor-Associated Factor 6 / genetics

Substances

  • 14-3-3 Proteins
  • CXCL1 protein, human
  • Chemokine CXCL1
  • Chemokines
  • Cytokines
  • Interleukin-17
  • Interleukin-6
  • TNF Receptor-Associated Factor 5
  • TNF Receptor-Associated Factor 6