# Regulation of proteolysis by deubiquiting enzyme in lung inflammatory disease

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $390,000

## Abstract

Abstract
An uncontrolled cytokine storm in lungs leads to detrimental effects such as neutrophil influx, capillary
leakage, tissue edema, and organ failure often manifested as pneumonia-induced acute lung injury (ALI).
Lysophosphatidic acid receptor 1 (LPA1) is a pro-inflammatory G protein coupled receptor, which induces pro-
inflammatory cytokine release through Gα-mediated signaling and interaction with endotoxin receptor, CD14.
LPA1 has been implicated in the pathogenesis of lung inflammatory disorders. Knockdown or inhibition of
LPA1 attenuates endotoxin- or bleomycin-induced lung injury and sepsis. We discovered that LPA1 stability is
regulated in the ubiquitin-lysosome system. Ubiquitin-specific protease 11 (USP11) deubiquitinates and
stabilizes LPA1, thus promoting LPA1-modulated pro-inflammatory effects. Knockdown of USP11 reduces
LPA1 stability and attenuates both LPA- and LPS-induced lung inflammation. This is the first to demonstrate
that destabilizing LPA1 reduces lung inflammation, and deubiquitinating enzyme contributes to the
pathogenesis of lung injury. We have developed a small blocking peptide (LDPep) to interrupt the interaction
between LPA1 and USP11, which specifically reduces LPA1 protein level, without altering expression of other
LPA receptors and USP11 target proteins. LDPep post-treatment lessens endotoxin-induced lung injury and
sepsis shock. This project will explore a novel therapeutic approach for treating inflammatory disorders like
ALI and sepsis. Execution of these studies will lay the groundwork for a significant mechanistic advance in the
molecular regulation of pro-inflammatory responses during severe infection. Results from these studies can
serve as the basis for further development of pharmacologic agents that destabilize LPA1, thereby reducing
severity of inflammatory diseases such as lung injury and sepsis.

## Key facts

- **NIH application ID:** 9912813
- **Project number:** 5R01HL131665-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Yutong Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2018-11-10 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9912813

## Citation

> US National Institutes of Health, RePORTER application 9912813, Regulation of proteolysis by deubiquiting enzyme in lung inflammatory disease (5R01HL131665-04). Retrieved via AI Analytics 2026-06-05 from https://api.ai-analytics.org/grant/nih/9912813. Licensed CC0.

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