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Ufm1 E3 ligase Ufl1 is essential for adaptive hypertrophy and ER stress response in the heart
Author(s) -
Li Jie,
Yue Guihua,
Ma Wenxia,
Li Huizhong,
Zhang Aizhen,
Li Faqian,
Li Honglin,
Su Huabo
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.958.3
Subject(s) - pressure overload , ubiquitin ligase , heart failure , dilated cardiomyopathy , medicine , muscle hypertrophy , downregulation and upregulation , cardiomyopathy , cardiology , fibrosis , endocrinology , ubiquitin , biology , cardiac hypertrophy , gene , biochemistry
Post‐translational modifications of proteins are important regulatory mechanisms of protein function. Protein modifications by Ufm1, a novel ubiquitin‐like protein, require Ufm1 E1 UBA5, E2 Ufc1 and E3 ligase Ufl1 and are emerging as a central theme in protein activity regulation. To date the significance of Ufm1 modification in health and disease is largely unknown. In this study, we reported that Ufl1 was down‐regulated in human failing hearts of ischemic cardiomyopathy and in the ischemic regions of mouse hearts subject to ischemia reperfusion injury. To investigate the effects of decreased Ufmylation in the heart, we generated mice with cardiomyocyte‐restricted deficiency of Ufl1 (Ufl1KO). Loss of Uf11 impaired Ufm1 conjugation and reduced the protein levels of its two known targets, RGDDK1 and C53, in mouse heart. The KO mice were viable and had no morphological abnormality at 2 months after birth. However, during ageing, Ufl1KO mice displayed reduced heart weight to body weight ratio, upregulation of cardiac fetal genes, increased apoptosis and increased fibrosis, which eventually led to left ventricular chamber dilatation, wall thinning and cardiac Huidysfunction at 6 months of age. When challenged by transverse aortic constriction (TAC)‐induced pressure overload, Ufl1KO mice quickly developed dilated cardiomyopathy and heart failure at 2 weeks post procedure without a prior phase of adaptive hypertrophy. RNA sequencing analysis revealed a significant alteration in the expression profile of ER stress‐related genes in Ufl1KO hearts, which was further confirmed by real‐time PCR analysis and western blots of several ER stress response factors. In primary cultured cardiomyocytes, knockdown of Ufl1 also blunted ER stress response and aggravated ER stress‐induced cell injury. Hence, our data demonstrate an essential role of Ufm1 modification in the heart under physiological and pathological conditions and reveal a critical role of Ufl1 in mediating adaptive ER stress response in cardiomyocytes. Support or Funding Information This work was supported in part by NIH grant R01HL124248 (to H.S.) and American Heart Association grant 11SDG6960011 (to H.S.).