# A Cul5 E3 ubiquitin ligase complex that prevents allergic asthma

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $434,730

## Abstract

Asthma is a chronic inflammatory disease of the airways that affects 26 million Americans and results in
approximately 3600 deaths per year in the US alone (1a). Asthma is a heterogeneous disease and both Th2
predominant and Th17 predominant forms have been described with different etiologies. While Th2 cytokines
are more common in patients with allergic asthma, there is variability among these patients in regards to the
types of Th2 cytokines found, severity of disease, and response to currently available therapies. IL-9 producing
Th9 cells are a new cytokine producing T cell that are often found in patients with allergic asthma and correlate
with disease severity. However, the mechanisms that regulate Th9 differentiation and function remain largly
unknown. We have identified a novel inhibitory pathway that limits the differentiation and pathogenicity of both
Th2 and Th9 cells and protects against airway remodeling in mice. This pathway is controlled by the E3 ubiquitin
ligase Cul5. Supporting this, we recently generated mice in which Cul5 was deleted only in T cells, and
determined that Cul5 limits airway remodeling after asthma induction. Specifically, we found that Cul5fl/flCD4-Cre
mice showed increased lung inflammation, eosinophilia, goblet cell hyperplasia and fibrosis following house dust
mite exposure. T cells from Cul5fl/flCD4-Cre mice were much more likely to Th2 and Th9 cells. Using a screen to
reveal Cul5 binding partners, we identified three substrate receptors that cooperate with Cul5 in T cells. Based
on these preliminary data we hypothesize that Cul5 associates with one or more of these substrate
receptors to ubiquitylate substrates and thus limits the differentiation of Th2 and Th9 cells and prevents
asthma. Based on our preliminary data, our long term goal is to develop novel therapeutic strategies that activate
the Cul5 pathway to turn Th2 and Th9 cells off in patients with asthma. However, to do this effectively we must
first determine 1) how Cul5 regulates T cell biology, 2) determine how interacting partners aid Cul5 function, and
3) delineate how, on a mechanistic level, Cul5 complexes limit T cell differentiation and pathogenicity (i.e identify
substrates). In this proposal we will determine key aspects of how Cul5 restricts T cell differentiation and function,
thus revealing the signaling pathways that allow Th9 cells to develop and drive asthma. Additionally, we will
identify regulatory mechanisms that promote the activation and function of Cul5. This information will provide
crucial information needed as we begin to develop therapies to target Cul5 to reduce the differentiation of Th2
and Th9 cells in allergic asthma.

## Key facts

- **NIH application ID:** 10049576
- **Project number:** 1R01AI148240-01A1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Paula Maria Oliver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $434,730
- **Award type:** 1
- **Project period:** 2020-05-18 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049576

## Citation

> US National Institutes of Health, RePORTER application 10049576, A Cul5 E3 ubiquitin ligase complex that prevents allergic asthma (1R01AI148240-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10049576. Licensed CC0.

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