# Regulation of ROR-gt in colonic inflammation

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $364,500

## Abstract

ABSTRACT
Dysregulated ROR-γt-mediated IL-17 expression is strongly associated with chronic inflammation. However, the
molecular mechanisms by which ROR-γt functions and how its stability is regulated remain elusive. Our
preliminary studies suggest that under steady-state conditions in the gut, ROR-γt is sumoylated in Th17 cells by
UBC9 (SUMO-E2 ligase) and TRIM55 (SUMO-E3 ligase). Additionally, we found that under steady-state
conditions, a novel NCOA6-HDAC2 repressor complex binds to ROR-γt. Upon T cell receptor stimulation, de-
sumoylation removes this repressor complex, resulting in IL-17 transcription. To prevent a prolonged Th17
response following stimulation, ROR-γt is phosphorylated by the kinase Pak2, which promotes Itch-mediated
ROR-γt ubiquitination and subsequent degradation. Based on these findings we hypothesize that that
ubiquitination and sumoylation of ROR-γt are critical molecular events that regulate Th17 responses and that can
be targeted therapeutically. In AIM 1, we will determine the mechanism by which sumoylation of ROR-γt
represses IL-17 transcription. By using newly generated CD4 T cell-specific TRIM55-/- mice, we will investigate
the mechanism by which the NCOA6/HDAC2 complex utilizes histone deacetylation to repress IL-17 expression.
In AIM 2, we will determine the mechanism by which phosphorylation promotes Itch-mediated ROR-γt
ubiquitination. Using Pak2-/- mice, we will investigate how the phosphorylation-dependent conformational change
of ROR-γt promotes its degradation. In AIM 3, we will target the Itch-ROR-γt-IL-17 pathway to inhibit excessive
inflammation. We will test the therapeutic potential of a small-molecule Itch activator to inhibit colonic
inflammation. Completion of these studies will lead to a clear understanding of the molecular mechanisms by
which ROR-γt function and its stability are regulated to prevent chronic inflammation. This knowledge should lead
to improved therapeutic strategies to target the ROR-γt-IL-17 pathway in human inflammatory diseases.

## Key facts

- **NIH application ID:** 9886237
- **Project number:** 5R01DK115668-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Venuprasad K Poojary
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,500
- **Award type:** 5
- **Project period:** 2018-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886237

## Citation

> US National Institutes of Health, RePORTER application 9886237, Regulation of ROR-gt in colonic inflammation (5R01DK115668-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9886237. Licensed CC0.

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