# Cardiac Pathophysiology of Proteasome Phosphoregulation

> **NIH NIH R01** · UNIVERSITY OF SOUTH DAKOTA · 2022 · $367,500

## Abstract

Heart disease is the leading cause of human mortality and morbidity. The ubiquitin-proteasome system (UPS)
is pivotal to protein quantity and quality control in the cell. UPS dysregulation, especially proteasome functional
insufficiency, plays a major role in the progression from a large subset of heart diseases to heart failure and,
accordingly, proteasome enhancement is implicated as a new strategy to treat heart disease with increased
proteotoxic stress (IPTS). To develop pharmacological means to enhance the proteasome, however, requires
understanding how proteasome activity is regulated as such regulatory mechanisms could potentially be
exploited to enhance the proteasome. Recent advances in cell biology show that phosphorylation of the
proteasome often increases proteasome activities but the in vivo physiological significance of proteasome
phosphoregulation has not been established. Thus, the goal of this project is to advance our understanding on
how specific proteasome phosphorylation regulates cardiac physiology and pathophysiology. Our pilot studies
have confirmed genetically in mice that phosphorylation of RPN6/PSMD11 at Ser14 is responsible for
proteasome activation by cAMP-dependent protein kinase (PKA). Our preliminary data further revealed that (1)
myocardial Ser14-phopshorylated Rpn6 (referred to as p-Rpn6) was markedly altered in mice with inherited
IPTS and mice subjected to myocardial ischemia or trans-aortic constriction (TAC) and (2) genetic blockade
and mimicry of p-Rpn6 substantially mitigated cardiac responses to various stressors. Hence, we propose to
test the central hypotheses that p-Rpn6 is essential to 26S Psm activation to meet the increased demand for
selective proteolysis in stressed cardiac muscle, via pursuit of these specific aims: (1) to determine the
necessity of p-Rpn6 in cardiac proteostasis and cardiac function at baseline, (2) to determine the role of
increased p-Rpn6 in the inherited heart disease with IPTS, and (3) to determine the role of increased p-Rpn6 in
an acquired heart disease with IPTS. New mouse models created with gene editing to block or mimic p-Rpn6,
as well as p-Rpn6 specific antibodies will be used along with a well-established UPS performance reporter.
Tandem mass-tags (TMT) based multiplexing coupled with tandem mass spectrometry will be used to profile
ubiquitinomes shaped by p-Rpn6 in stressed hearts. This research will provide the ultimate in vivo
demonstration for the molecular basis of PKA-elicited proteasome activation, determine unequivocally for the
first time the (patho)physiological significance of this key proteasome phosphoregulation in intact animals, and
illustrate whether this regulation can be exploited for therapeutic purposes.

## Key facts

- **NIH application ID:** 10435491
- **Project number:** 5R01HL153614-03
- **Recipient organization:** UNIVERSITY OF SOUTH DAKOTA
- **Principal Investigator:** XUEJUN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,500
- **Award type:** 5
- **Project period:** 2020-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435491

## Citation

> US National Institutes of Health, RePORTER application 10435491, Cardiac Pathophysiology of Proteasome Phosphoregulation (5R01HL153614-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10435491. Licensed CC0.

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