# Determining role of 14-3-3zeta in IL-17A signaling

> **NIH NIH R01** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2024 · $790,019

## Abstract

Summary
Interleukin-17 (IL-17), a pro-inflammatory cytokine, is pathogenic in autoimmune diseases such as
Inflammatory Arthritis (IA). IA affects more than 1% of the worldwide population and remains incurable to date1.
Ectopic IL17A expression in mice induces IA phenotype and provides a model to study mechanisms2. Activation
of IL-17A receptor (IL-17R) recruits a signaling complex consisting of Act1 and TRAFs (Tumor Necrosis Factor
Receptor Associated Factors). Activation of TRAF6 or TRAF2/5 results in transcriptional (IL6) and post-
transcriptional (CXCL1) outcomes of IL-17A cytokine. TRAFs often interact with each other and influence
signaling outcomes. The crosstalk between the TRAF6 and TRAF2/5 branches in IL-17A signaling remains
unknown. Our recent PNAS publications showed that 14-3-3z is a novel component of IL-17R signaling and
suppresses IA. In IL-17A signaling, 14-3-3z connects the two TRAF branches, inhibits TRAF5 but promotes
TRAF6. There are two motifs on 14-3-3z that interact and show specificity to TRAF5 and TRAF6 binding. We
also showed that TRAF5 inhibits TRAF6-dependent IL-17A signaling. Our new preliminary data show that 14-
3-3z modifies TRAFs and their interactions with other cellular proteins, thus providing clues to its mechanism.
Our long-term goal is to understand how 14-3-3z bridges TRAFs in IL-17R signaling and diseases. We
hypothesize that “14-3-3z has a dual role in IL-17 signaling by executing the opposing functions of TRAFs,
leading to the prevention of IA.” We propose to investigate the molecular mechanisms and physiological
relevance of the 14-3-3z-TRAF axis in regulating IL-17R signaling and inflammatory arthritis with three specific
aims. The first two aims will examine how 14-3-3z regulates TRAF5 and TRAF6 activity, connects two branches,
and gain an in-depth understanding of 14-3-3z’s function in IL-17R signaling. In the third aim, we will examine
the physiological relevance of the 14-3-3z-TRAF axis using an innovative IL-17A gene transfer model to study
14-3-3z role in chronic IL-17A and IA pathogenesis using 14-3-3z knockout animals. Successful completion of
this proposal will provide mechanistic insight into how 14-3-3z modifies TRAF proteins and their activity,
regulates IL-17R signaling, and suppresses IA. This study is innovative because by studying 14-3-3z’s role in
TRAF biology, we examine the molecular basis of a novel fundamental immune regulatory axis in IL-17R
signaling and IA. Our study is significant because understanding 14-3-3z action on TRAFs advances our
fundamental knowledge of protein biochemistry, immunology, IL-17R signaling, IA pathogenesis, and other
autoimmune diseases. IA is a challenging disease with limited therapeutic options; therefore, a deeper
understanding of IA pathogenesis is desired. And, as TRAFs play a critical role in many receptor signaling, the
implications of 14-3-3z functions go beyond IL-17R signaling to many other autoimmune and infectious
diseases.

## Key facts

- **NIH application ID:** 10945391
- **Project number:** 1R01AI184880-01
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** Ritu Chakravarti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $790,019
- **Award type:** 1
- **Project period:** 2024-06-10 → 2025-02-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10945391

## Citation

> US National Institutes of Health, RePORTER application 10945391, Determining role of 14-3-3zeta in IL-17A signaling (1R01AI184880-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10945391. Licensed CC0.

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