# The Deubiquitinase CYLD Controls Multiple Cell Death Pathways in the Heart

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $388,750

## Abstract

Project Summary/Abstract
Cardiac cell death by apoptosis and/or necrosis is a hallmark of cardiac ischemic injury, pathological remodeling,
and end-stage heart failure. In contrast to apoptosis, the role of necrosis in the pathogenesis of heart disease
has been largely understudied. Emerging evidence has identified several forms of “programmed necrosis”, such
as death receptor-mediated necrosis (termed “necroptosis”), mitochondria-mediated necrosis, and oxidative
stress-induced necrosis. How programmed necrosis is regulated in the heart remains largely unknown, and
preventing necrosis is still an important challenge. Moreover, currently no molecular strategies are available to
simultaneously target multiple cell death processes in heart disease. Here, our preliminary studies identified an
unexpected role for CYLD (cylindromatosis), a lysine 63 (K63)-specific deubiquitinase, as a key regulator of
multiple cell death pathways in cardiomyocytes, including apoptosis, necroptosis, and oxidative stress-induced
necrosis. Intriguingly, CYLD expression was markedly upregulated in the heart following ischemic injury. Using
Cyld knockout and transgenic mouse models, our preliminary data further show that ablation of CYLD
attenuated, whereas overexpression of CYLD exacerbated, cardiac ischemic injury. Importantly, ablation of
CYLD inhibited apoptosis, necroptosis, and necrosis in cardiomyocytes, whereas overexpression of CYLD
showed the opposite effect. Mechanistically, our data reveal a K63-linked polyubiquitination (K63-Ub) dependent
cell death signaling mechanism whereby CYLD controls the ubiquitination status and activity of three cell death
regulators: TRAF2, TAK1 and AKT/PKB. Therefore, we hypothesize the deubiquitinase CYLD is a key regulator
of multiple cell death pathways and a promising therapeutic target for cardiac ischemic injury and remodeling.
Using genetic loss- and gain-of-function strategies, we will address two specific aims: Aim 1) To investigate the
novel role of CYLD as a key regulator of myocardial cell death, ischemic injury, and remodeling using Cyld
knockout and transgenic models and AAV9-shCYLD vectors. Aim 2) To define a CYLD-mediated, K63-Ub
dependent cell death signaling network regulating apoptosis, necroptosis, and necrosis in cardiomyocytes. This
project investigates a novel CYLD-mediated cell death signaling network in the heart and its functional relevance
in cardiac ischemic injury and remodeling. Moreover, the proposed studies will define a K63-Ub dependent
mechanism regulating apoptosis, necroptosis, and necrosis, which constitutes a new paradigm of cell death
regulation. These studies also have important translational implications by providing new anti-cell death
strategies, given our preliminary results revealing CYLD as a molecular target for multiple cell death processes.

## Key facts

- **NIH application ID:** 10815690
- **Project number:** 5R01HL160767-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Qinghang Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815690

## Citation

> US National Institutes of Health, RePORTER application 10815690, The Deubiquitinase CYLD Controls Multiple Cell Death Pathways in the Heart (5R01HL160767-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10815690. Licensed CC0.

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