# DCAF7/HDAC4/TFEB axis in acute lung injury

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $471,666

## Abstract

ABSTRACT
Acute Respiratory Distress Syndrome (ARDS) or Acute Lung Injury (ALI) is an acute lung
inflammatory process that is associated with an overall mortality ranging from 35% to 50%, and
pneumonia is one of the most frequent causes. The central pathophysiology of ARDS/ALI is
injury to the epithelium in the airway/alveoli, and overproduction of inflammatory factors in lung
tissue. Mitochondria provide the energy supply for numerous cellular activities, and are also the
powerhouses of immunity. Bacterial infection impairs mitochondria, and dysfunctional
mitochondria need to be cleared through lysosomal degradation, a process termed
autophagy/mitophagy. Endogenous damage-associated molecular patterns DAMPs (mtDNA,
ATP, ROS) released from damaged mitochondria activate inflammasomes and inflammation.
We identify that the deficiency of TFEB, a master transcription factor of autophagy and
lysosome biogenesis, impairs mitophagy leading to deleterious DAMP and pro-inflammatory
cytokines release, thus activating inflammasomes and inflammation. Through screening a
library of FDA-approved drugs (1068 drugs), we identify that the HDAC inhibitor Panobinostat
elevates TFEB protein abundance by inhibiting HDAC4. Through unbiased proteomic mass
spectrometry analysis, we identify DCAF7 as a substrate receptor for CRL4 ubiquitin E3 ligase
recruiting TFEB. DCAF7 overexpression dose-dependently decreases TFEB protein abundance.
DCAF7 knockdown prolongs TFEB protein half-life and accumulates its protein levels in the
nucleus. Specifically, our preliminary data suggest that 1) bacterial infection decreases TFEB
protein levels; 2) TFEB deficiency aggravates harmful DAMP and cytokine release that in turn
postpone inflammation resolution; 3) Panobinostat-mediated HDAC4 inhibition preserves TFEB
proteins and alleviates bacteria-induced lung inflammation; 4) CRL4 ubiquitin E3 ligase subunit
DCAF7 recruits TFEB for proteasomal degradation; 5) a novel small molecule DCAF7 inhibitor
BC1753 protects TFEB against degradation. These data led to our hypothesis that inhibiting
DCAF7/HDAC4 axis to prevent TFEB from degradation will attenuate bacterial infection-induced
lung inflammation and improve inflammation resolution. We will conduct mechanistic studies to
determine if TFEB exerts an essential role in bacterial lung inflammation through inhibiting
necroptosis (Aim 1). We will examine the role of HDAC4 in regulating TFEB protein stability
and lung inflammatory responses in experimental ALI models (Aim 2). We will also test if the
small molecule DCAF7 inhibitor alleviates bacterial lung inflammation through preventing TFEB
protein degradation (Aim 3). This will be the first study to intervene DCAF7/HDAC4/TFEB axis
for inflammatory disease such as ARDS/ALI. Execution of this project will lay the groundwork for
a fundamental, paradigm-changing therapeutic advance to regulate innate immunity and treat
lung inflammation that will ultimately set the stage for a new translational i...

## Key facts

- **NIH application ID:** 10183301
- **Project number:** 5R01HL142777-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Yuan Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $471,666
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183301

## Citation

> US National Institutes of Health, RePORTER application 10183301, DCAF7/HDAC4/TFEB axis in acute lung injury (5R01HL142777-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10183301. Licensed CC0.

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