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

Jenna McGowan, Cara Peter, Joshua Kim, Sonam Popli, Brent Veerman, Jessica Saul-McBeth, Heather Conti, Shondra M. Pruett-Miller, Saurabh Chattopadhyay, Ritu Chakravarti

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish
Pages (from-to)25008-25017
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number40
DOIs
StatePublished - Oct 6 2020

Bibliographical note

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Keywords

  • 14-3-3ζ
  • IL-17A
  • TRAF

ASJC Scopus subject areas

  • General

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