# NEDD4 IN T HELPER CELL DEVELOPMENT AND AUTOIMMUNITY

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $477,437

## Abstract

Project Summary
T helper (Th) 17 cells are thought to play a key role in the development and pathogenesis of autoimmune
diseases, including multiple sclerosis (MS) and its murine models, experimental autoimmune encephalomyelitis
(EAE), rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. The development
of Th17 cells is controlled by RORγt, and small molecules that target RORγt attenuate Th17 response and the
severity of EAE and cutaneous inflammation. However, the regulation of RORγt activity during Th17 cell
differentiation by TCR signaling is largely unknown. Nedd4 (also known as Nedd4-1, neuronal precursor cell-
expressed developmentally down-regulated 4) is a HECT-type E3 ubiquitin ligase. Through sequence analysis,
we identified a PPLYKEL motif, an extended Nedd4 WW domain-binding motif, at the carboxyl terminus of the
RORγt ligand-binding domain, suggesting that RORγt may be a binding partner of Nedd4. Indeed, Nedd4 is
tyrosine-phosphorylated and activated upon TCR/CD28 stimulation and binds to RORγt which undergoes K63-
linked poly-ubiquitination. This ubiquitination is abrogated in T cells lacking Nedd4. Further analysis showed that
although Nedd4 deficiency does not impair Th1, Th2, and inducible regulatory T cell differentiation, Th17 cell
differentiation is greatly compromised in the absence of Nedd4. In support of this observation, mice deficient for
Nedd4, or deficient for Nedd4 in T cells, have ameliorated EAE with impaired Th17 responses. Based upon these
preliminary data, we hypothesize that upon T cell antigenic stimulation Nedd4 is activated by Src kinase(s), and
targets RORγt for K63-linked polyubiquitination, thus regulating Th17 responses and the susceptibility to EAE in
mice and possibly MS in humans. In this proposal, we will investigate 1) How Nedd4 potentiates Th17 cell
differentiation in vitro; 2) Whether Nedd4 promotes Th17 responses in vivo, regulating the susceptibility to EAE;
and 3) How Nedd4 is activated in T cells in response to TCR/CD28 stimulation. The identification of Nedd4 as a
key molecule regulating Th17 responses and the pathogenesis of EAE, and possibly MS, will have potential
implications for using this molecule as a therapeutic target to treat autoimmune diseases involving Th17.

## Key facts

- **NIH application ID:** 9939420
- **Project number:** 5R01AI090901-16
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** THOMAS J WALDSCHMIDT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $477,437
- **Award type:** 5
- **Project period:** 2017-12-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939420

## Citation

> US National Institutes of Health, RePORTER application 9939420, NEDD4 IN T HELPER CELL DEVELOPMENT AND AUTOIMMUNITY (5R01AI090901-16). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9939420. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*