# ISGylation regulates lung endothelial inflammation

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $534,244

## Abstract

Abstract
 Excessive lung microvascular endothelial inflammation is a pathological hallmark of acute
respiratory distress syndrome (ARDS). Upon inflammatory stimuli, lung endothelial cells (ECs)
increase chemokine and adhesion molecule expression, such as IL-6, and intercellular adhesion
molecule 1, ultimately causing neutrophil accumulation at the site of inflammation, endothelial
barrier dysfunction, and lung tissue damage in acute lung injury and sepsis. Nuclear
transcriptional factor κB (NF-κB) plays a pivotal role in EC inflammation. Inflammatory stimuli
trigger phosphorylation of NF-κB component p65, leading to increase p65 transcriptional activity.
We revealed that NF-κBp65 can be ISGylated. The ISGylated p65 is inactive in the resting ECs.
We also discovered that SCFFBXL19 E3 ligase catalyzes ISGylation of p65, impedes p65
phosphorylation, and mitigates lung EC inflammation. These observations led us to hypothesize
that p65 ISGylation by SCFFBXL19 dampens its phosphorylation, transcriptional activation, and lung
EC inflammation; and increases in FBXL19 stability mitigates lung EC inflammation through
reducing NF-kB activation. To better understand the new modification of p65, in this proposal, we
will determine molecular mechanisms by which SCFFBXL19 catalyzes p65 ISGylation and its role in
human lung microvascular EC inflammation. And then, we will determine the molecular
mechanisms by which p65 ISGylation impedes its phosphorylation and activation in human lung
microvascular ECs. Lastly, we will determine if stabilization of FBXL19 alleviates lung EC
inflammation in murine models of acute lung injury and sepsis. This application will be the first to
characterize SCFFBXL19-mediated ISGylation of NF-κBp65 and determine its role in the regulation
of p65 phosphorylation, transcriptional activation, and lung EC inflammation in acute lung injury
and sepsis.

## Key facts

- **NIH application ID:** 10394303
- **Project number:** 5R01HL157164-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Yutong Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $534,244
- **Award type:** 5
- **Project period:** 2021-04-20 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10394303

## Citation

> US National Institutes of Health, RePORTER application 10394303, ISGylation regulates lung endothelial inflammation (5R01HL157164-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10394303. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*