Ufm1-Specific Ligase Ufl1 Regulates Endoplasmic Reticulum Homeostasis and Protects Against Heart Failure

Jie Li, Guihua Yue, Wenxia Ma, Aizhen Zhang, Jianqiu Zou, Yafei Cai, Xiaoli Tang, Jun Wang, Jinbao Liu, Honglin Li, Huabo Su

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

BACKGROUND: Defects in protein homeostasis are sufficient to provoke cardiac remodeling and dysfunction. Although posttranslational modifications by ubiquitin and ubiquitin-like proteins are emerging as an important regulatory mechanism of protein function, the role of Ufm1 (ubiquitin-fold modifier 1)-a novel ubiquitin-like protein-has not been explored in either the normal or stressed heart. METHODS AND RESULTS: Western blotting revealed that Ufl1 (Ufm1-specific E3 ligase 1)-an enzyme essential for Ufm1 modification-was increased in hypertrophic mouse hearts but reduced in the failing hearts of patients with dilated cardiomyopathy. To determine the functional role of Ufl1 in the heart, we generated a cardiac-specific knockout mouse and showed that Ufl1-deficient mice developed age-dependent cardiomyopathy and heart failure, as indicated by elevated cardiac fetal gene expression, increased fibrosis, and impaired cardiac contractility. When challenged with pressure overload, Ufl1-deficient hearts exhibited remarkably greater hypertrophy, exacerbated fibrosis, and worsened cardiac contractility compared with control counterparts. Transcriptome analysis identified that genes associated with the endoplasmic reticulum (ER) function were dysregulated in Ufl1-deficient hearts. Biochemical analysis revealed that excessive ER stress preceded and deteriorated along with the development of cardiomyopathy in Ufl1-deficient hearts. Mechanistically, Ufl1 depletion impaired (PKR-like ER-resident kinase) signaling and aggravated cardiomyocyte cell death after ER stress. Administration of the chemical ER chaperone tauroursodeoxycholic acid to Ufl1-deficient mice alleviated ER stress and attenuated pressure overload-induced cardiac dysfunction. CONCLUSIONS: Our results advance a novel concept that the Ufm1 system is essential for cardiac homeostasis through regulation of ER function and that upregulation of myocardial Ufl1 could be protective against heart failure.

Original languageEnglish (US)
Pages (from-to)e004917
JournalCirculation. Heart failure
Volume11
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Ubiquitin-Protein Ligases
Ligases
Ubiquitin
Endoplasmic Reticulum
Homeostasis
Heart Failure
Endoplasmic Reticulum Stress
Ubiquitins
Cardiomyopathies
Fibrosis
Pressure
Dilated Cardiomyopathy
Gene Expression Profiling
Post Translational Protein Processing
Cardiac Myocytes
Knockout Mice
Hypertrophy
Proteins
Cell Death
Phosphotransferases

Keywords

  • endoplasmic reticulum stress
  • heart failure
  • hypertrophy
  • ubiquitin-like proteins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Ufm1-Specific Ligase Ufl1 Regulates Endoplasmic Reticulum Homeostasis and Protects Against Heart Failure. / Li, Jie; Yue, Guihua; Ma, Wenxia; Zhang, Aizhen; Zou, Jianqiu; Cai, Yafei; Tang, Xiaoli; Wang, Jun; Liu, Jinbao; Li, Honglin; Su, Huabo.

In: Circulation. Heart failure, Vol. 11, No. 10, 01.10.2018, p. e004917.

Research output: Contribution to journalArticle

Li, Jie ; Yue, Guihua ; Ma, Wenxia ; Zhang, Aizhen ; Zou, Jianqiu ; Cai, Yafei ; Tang, Xiaoli ; Wang, Jun ; Liu, Jinbao ; Li, Honglin ; Su, Huabo. / Ufm1-Specific Ligase Ufl1 Regulates Endoplasmic Reticulum Homeostasis and Protects Against Heart Failure. In: Circulation. Heart failure. 2018 ; Vol. 11, No. 10. pp. e004917.
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T1 - Ufm1-Specific Ligase Ufl1 Regulates Endoplasmic Reticulum Homeostasis and Protects Against Heart Failure

AU - Li, Jie

AU - Yue, Guihua

AU - Ma, Wenxia

AU - Zhang, Aizhen

AU - Zou, Jianqiu

AU - Cai, Yafei

AU - Tang, Xiaoli

AU - Wang, Jun

AU - Liu, Jinbao

AU - Li, Honglin

AU - Su, Huabo

PY - 2018/10/1

Y1 - 2018/10/1

N2 - BACKGROUND: Defects in protein homeostasis are sufficient to provoke cardiac remodeling and dysfunction. Although posttranslational modifications by ubiquitin and ubiquitin-like proteins are emerging as an important regulatory mechanism of protein function, the role of Ufm1 (ubiquitin-fold modifier 1)-a novel ubiquitin-like protein-has not been explored in either the normal or stressed heart. METHODS AND RESULTS: Western blotting revealed that Ufl1 (Ufm1-specific E3 ligase 1)-an enzyme essential for Ufm1 modification-was increased in hypertrophic mouse hearts but reduced in the failing hearts of patients with dilated cardiomyopathy. To determine the functional role of Ufl1 in the heart, we generated a cardiac-specific knockout mouse and showed that Ufl1-deficient mice developed age-dependent cardiomyopathy and heart failure, as indicated by elevated cardiac fetal gene expression, increased fibrosis, and impaired cardiac contractility. When challenged with pressure overload, Ufl1-deficient hearts exhibited remarkably greater hypertrophy, exacerbated fibrosis, and worsened cardiac contractility compared with control counterparts. Transcriptome analysis identified that genes associated with the endoplasmic reticulum (ER) function were dysregulated in Ufl1-deficient hearts. Biochemical analysis revealed that excessive ER stress preceded and deteriorated along with the development of cardiomyopathy in Ufl1-deficient hearts. Mechanistically, Ufl1 depletion impaired (PKR-like ER-resident kinase) signaling and aggravated cardiomyocyte cell death after ER stress. Administration of the chemical ER chaperone tauroursodeoxycholic acid to Ufl1-deficient mice alleviated ER stress and attenuated pressure overload-induced cardiac dysfunction. CONCLUSIONS: Our results advance a novel concept that the Ufm1 system is essential for cardiac homeostasis through regulation of ER function and that upregulation of myocardial Ufl1 could be protective against heart failure.

AB - BACKGROUND: Defects in protein homeostasis are sufficient to provoke cardiac remodeling and dysfunction. Although posttranslational modifications by ubiquitin and ubiquitin-like proteins are emerging as an important regulatory mechanism of protein function, the role of Ufm1 (ubiquitin-fold modifier 1)-a novel ubiquitin-like protein-has not been explored in either the normal or stressed heart. METHODS AND RESULTS: Western blotting revealed that Ufl1 (Ufm1-specific E3 ligase 1)-an enzyme essential for Ufm1 modification-was increased in hypertrophic mouse hearts but reduced in the failing hearts of patients with dilated cardiomyopathy. To determine the functional role of Ufl1 in the heart, we generated a cardiac-specific knockout mouse and showed that Ufl1-deficient mice developed age-dependent cardiomyopathy and heart failure, as indicated by elevated cardiac fetal gene expression, increased fibrosis, and impaired cardiac contractility. When challenged with pressure overload, Ufl1-deficient hearts exhibited remarkably greater hypertrophy, exacerbated fibrosis, and worsened cardiac contractility compared with control counterparts. Transcriptome analysis identified that genes associated with the endoplasmic reticulum (ER) function were dysregulated in Ufl1-deficient hearts. Biochemical analysis revealed that excessive ER stress preceded and deteriorated along with the development of cardiomyopathy in Ufl1-deficient hearts. Mechanistically, Ufl1 depletion impaired (PKR-like ER-resident kinase) signaling and aggravated cardiomyocyte cell death after ER stress. Administration of the chemical ER chaperone tauroursodeoxycholic acid to Ufl1-deficient mice alleviated ER stress and attenuated pressure overload-induced cardiac dysfunction. CONCLUSIONS: Our results advance a novel concept that the Ufm1 system is essential for cardiac homeostasis through regulation of ER function and that upregulation of myocardial Ufl1 could be protective against heart failure.

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