# The NRF2-p62 Axis in the Cross-Talk between Proteasomal and Lysosomal Degradation

> **NIH NIH R01** · UNIVERSITY OF SOUTH DAKOTA · 2020 · $350,625

## Abstract

Heart failure is a leading cause of human mortality and morbidity without a cure. Protein degradation by the
ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) is pivotal to cardiac protein
quality control which acts to minimize the level and toxicity of misfolded proteins in cardiomyocytes. Protein
quality control inadequacy resulting from UPS and ALP dysfunctions is implicated in the development of heart
failure from a variety of heart diseases including pressure overload (PO) disorders. Proteasome inhibition
activates ALP while ALP impairment can compromise UPS performance, suggesting an intricate interplay
between UPS and ALP dysfunctions. However, such interplay in diseased hearts and its underlying
mechanisms remain to be defined. Therefore the long term goal of this research project is to delineate the
molecular basis of UPS-ALP crosstalk. Literature and our pilot studies suggest that NRF2 (nuclear factor-
erythroid 2-related factor 2) and its target gene p62/SQSTM1 may act as a molecular link in the impairment of
UPS performance by ALP insufficiency but this remains to be established in the heart. Hence, we propose to
determine the role of the Nrf2-p62 axis in regulating ALP-UPS cross-talk in pressure overloaded hearts. The
central hypothesis to be tested is that activation of the Nrf2-p62 axis plays a major mediating role in the
impairment of UPS performance by ALP insufficiency in pressure overloaded hearts. We will pursue 2
specific aims. Aim 1 will determine the role of Nrf2 in the induction of cardiac UPS impairment and maladaptive
remodeling by ALP impairment in PO hearts. Aim 2 will investigate the molecular mechanism by which Nrf2
exacerbates cardiac injury in ALP insufficient hearts, testing the hypothesis that induction of p62 by Nrf2
impairs UPS performance in ALP deficient hearts. This project will likely provide new mechanistic insight into
UPS-ALP interplay in the heart and establish a new concept that enhancing ALP while activating Nrf2 is a
better strategy than Nrf2 activation alone for treating heart disease.

## Key facts

- **NIH application ID:** 9891075
- **Project number:** 5R01HL131667-04
- **Recipient organization:** UNIVERSITY OF SOUTH DAKOTA
- **Principal Investigator:** Taixing Cui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $350,625
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891075

## Citation

> US National Institutes of Health, RePORTER application 9891075, The NRF2-p62 Axis in the Cross-Talk between Proteasomal and Lysosomal Degradation (5R01HL131667-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891075. Licensed CC0.

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