Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex.
Calcineurin, which binds to the Z-disc in cardiomyocytes via alpha-actinin, promotes cardiac hypertrophy in response to numerous pathologic stimuli. However, the endogenous mechanisms regulating calcineurin activity in cardiac muscle are not well understood. We demonstrate that a muscle-specific F-box protein called atrogin-1, or muscle atrophy F-box, directly interacts with calcineurin A and alpha-actinin-2 at the Z-disc of cardiomyocytes. Atrogin-1 associates with Skp1, Cul1, and Roc1 to assemble an SCF(atrogin-1) complex with ubiquitin ligase activity. Expression of atrogin-1 decreases levels of calcineurin A and promotes its ubiquitination. Moreover, atrogin-1 attenuates agonist-induced calcineurin activity and represses calcineurin-dependent transactivation and NFATc4 translocation. Conversely, downregulation of atrogin-1 using adenoviral small interfering RNA (siRNA) expression enhances agonist-induced calcineurin activity and cardiomyocyte hypertrophy. Consistent with these cellular observations, overexpression of atrogin-1 in hearts of transgenic mice reduces calcineurin protein levels and blunts cardiac hypertrophy after banding of the thoracic aorta. These studies indicate that the SCF(atrogin-1) ubiquitin ligase complex interacts with and represses calcineurin by targeting calcineurin for ubiquitin-mediated proteolysis, leading to inhibition of cardiac hypertrophy in response to pathologic stimuli.
Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, NC 27599-7126, USA.
Hui-Hua
HH
Li
Vishram
V
Kedar
Chunlian
C
Zhang
Holly
H
McDonough
Ranjana
R
Arya
Da-Zhi
DZ
Wang
Cam
C
Patterson
D000185:Actinin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D004452:Echocardiography; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins; D032383:Myocytes, Cardiac / Q000166:cytology / Q000473:pathology / Q000502:physiology; D009929:Organ Size; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C401401:ACTN2 protein, human; C498529:Actn2 protein, mouse; C498530:Actn2 protein, rat; D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D044783:F-Box Proteins; D046911:Macromolecular Substances; D009124:Muscle Proteins; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D000185:Actinin; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; D019703:Calcineurin