Loss of muscle-specific RING-finger 3 predisposes the heart to cardiac rupture after myocardial infarction.
RING-finger proteins commonly function as ubiquitin ligases that mediate protein degradation by the ubiquitin-proteasome pathway. Muscle-specific RING-finger (MuRF) proteins are striated muscle-restricted components of the sarcomere that are thought to possess ubiquitin ligase activity. We show that mice lacking MuRF3 display normal cardiac function but are prone to cardiac rupture after acute myocardial infarction. Cardiac rupture is preceded by left ventricular dilation and a severe decrease in cardiac contractility accompanied by myocyte degeneration. Yeast two-hybrid assays revealed four-and-a-half LIM domain (FHL2) and gamma-filamin proteins as MuRF3 interaction partners, and biochemical analyses showed these proteins to be targets for degradation by MuRF3. Accordingly, FHL2 and gamma-filamin accumulated to abnormal levels in the hearts of mice lacking MuRF3. These findings reveal an important role of MuRF3 in maintaining cardiac integrity and function after acute myocardial infarction and suggest that turnover of FHL2 and gamma-filamin contributes to this cardioprotective function of MuRF3.
Fielitz
Jens
J
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
van Rooij
Eva
E
Spencer
Jeffrey A
JA
Shelton
John M
JM
Latif
Shuaib
S
van der Nagel
Roel
R
Bezprozvannaya
Svetlana
S
de Windt
Leon
L
Richardson
James A
JA
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
D000818:Animals; D003285:Contractile Proteins / Q000378:metabolism; D004452:Echocardiography; D064448:Filamins; D018398:Homeodomain Proteins / Q000378:metabolism; D060850:LIM-Homeodomain Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D008957:Models, Genetic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012518:Sarcomeres / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015854:Up-Regulation
D003285:Contractile Proteins; C491382:Fhl2 protein, mouse; D064448:Filamins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C413644:Rnf30 protein, mouse; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases