# Deubiquitinating and inhibiting Hsp90 by USP40 mitigates lung injury

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $412,505

## Abstract

Abstract
 Acute lung injury (ALI) is a life-threatening inflammatory lung condition that is most commonly
caused by pneumonia or sepsis. ALI-related mortality remains at unexpectedly high levels. Hence,
a new therapeutic strategy for ALI is needed. Uncontrolled cytokine storm, neutrophil influx into
alveolar spaces, and leakage from capillaries are the hallmarks of ALI, thus, a promising
therapeutic strategy in the acute phase of ALI is to restrain pro-inflammatory responses and
capillary barrier disruption simultaneously. Heat shock protein 90 (Hsp90) has been known to
contribute to the pathogenesis of ALI by promoting pro-inflammatory responses in a variety of
lung cell types and increasing endothelial cell (EC) permeability. Inhibition of Hsp90 activity by
small molecule inhibitors have been shown to reduce the severity of ALI in animal models
dramatically; however, molecular regulation of Hsp90 has not been well studied. We discovered
that Hsp90 can be mono-ubiquitinated and the mono-ubiquitination may compete with acetylation
of Hsp90 to increase Hsp90 activity. We identified that USP40, a DUB, deubiquitinates Hsp90,
thus resulting in inhibiting Hsp90. We hypothesize that deubiquitinating and inhibiting Hsp90 by
USP40 mitigate lung injury by suppressing pro-inflammatory responses and preserving EC barrier
integrity. We will determine the molecular mechanisms by which USP40 deubiquitinates and
inactivates Hsp90. Then, we will focus on determining the molecular mechanisms by which
USP40 mitigates pro-inflammatory responses and pulmonary EC barrier disruption through
deubiquitination of Hsp90. Lastly, we will determine if USP40 de-mono-ubiquitination of Hsp90
plays a protective role in murine models of ALI. These studies will be the first to elucidate the
protective role of inactivating Hsp90 by USP40 against lung injury.

## Key facts

- **NIH application ID:** 10168603
- **Project number:** 5R01HL151513-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** JING ZHAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,505
- **Award type:** 5
- **Project period:** 2020-06-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168603

## Citation

> US National Institutes of Health, RePORTER application 10168603, Deubiquitinating and inhibiting Hsp90 by USP40 mitigates lung injury (5R01HL151513-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10168603. Licensed CC0.

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