TY - JOUR
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
N1 - Funding Information:
We would like to thank Dr David Fulton, Vascular Biology Center at Medical College of Georgia, Augusta University, for critically reading the manuscript and suggesting substantial improvements.
Publisher Copyright:
© 2018 American Heart Association, Inc.
PY - 2018/1/8
Y1 - 2018/1/8
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.
KW - Endoplasmic reticulum stress
KW - Heart failure
KW - Hypertrophy
KW - Ubiquitin-like proteins
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U2 - 10.1161/CIRCHEARTFAILURE.118.004917
DO - 10.1161/CIRCHEARTFAILURE.118.004917
M3 - Article
C2 - 30354401
AN - SCOPUS:85055595892
SN - 1941-3289
VL - 11
JO - Circulation: Heart Failure
JF - Circulation: Heart Failure
IS - 10
M1 - 004917
ER -