Premium
CHIP mono‐ubiquitination activity – effects on cardiovascular metabolism and AMPK activity
Author(s) -
Schisler Jonathan C.,
Willis Monte S.,
Patterson Cam
Publication year - 2010
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.24.1_supplement.115.1
Subject(s) - ampk , protein kinase a , mitochondrial biogenesis , amp activated protein kinase , chemistry , ubiquitin , endocrinology , medicine , kinase , muscle hypertrophy , microbiology and biotechnology , mitochondrion , biology , biochemistry , gene
CHIP coordinates protein quality control through its ability to directly ubiquitinate proteins and interaction with cellular chaperones. Mice lacking CHIP expression exhibit exaggerated cardiac hypertrophy in response to one week of pressure overload using transverse aortic banding: a two‐fold increase in heart:body weight and a 30 ± 3% decrease in fractional shortening compared to wild‐type mice. Given the loss of contractile function despite an increase in muscle mass, we further examined the metabolic state of CHIP −/− hearts. After one week of banding, CHIP −/− mice had a 43 ± 10% decrease in mitochondrial biogenesis and 49 ± 2% and 61 ± 7% decreases in steady‐state ATP levels and ex vivo rates of ATP generation, respectively. AMP‐activated protein kinase (AMPK) functions as a cardiac energy sensor, increasing catabolic pathways and mitochondrial biogenesis during times of energy depletion. Surprisingly, there was a 40 ± 4% and 47 ± 6% decrease in the active form and activity of AMPK in banded CHIP −/− hearts, respectively. In cell culture, CHIP is necessary and sufficient for AMPK activation and mono‐ubiquitinates the α, β, and γ subunits of AMPK in vitro . Surprisingly mono‐ubiqutination of AMPKα2 increases kinase activity two‐fold, suggesting for the first time that mono‐ubiquitination can directly regulate kinase activity and demonstrates the vital role of CHIP in cardiac hypertrophy and energy homeostasis.