Abstract
The z-disc is a structural component at the lateral borders of the sarcomere and is important for mechanical stability and contractility of both cardiac and skeletal muscles. Of note, the sarcomeric z-disc also represents a nodal point in cardiomyocyte function and signaling. Mutations of numerous z-disc proteins are associated with cardiomyopathies and muscle diseases. To identify additional z-disc proteins that might contribute to cardiac disease, we employed an in silico screen for cardiac-enriched cDNAs. This screen yielded a previously uncharacterized protein named cardiac-enriched FHL2-interacting protein (CEFIP), which exhibited a heart- and skeletal muscle-specific expression profile. Importantly, CEFIP was located at the z-disc and was up-regulated in several models of cardiomyopathy. We also found that CEFIP overexpression induced the fetal gene program and cardiomyocyte hypertrophy. Yeast two-hybrid screens revealed that CEFIP interacts with the calcineurin-binding protein four and a half LIM domains 2 (FHL2). Because FHL2 binds calcineurin, a phosphatase controlling hypertrophic signaling, we examined the effects of CEFIP on the calcineurin/nuclear factor of activated T-cell (NFAT) pathway. These experiments revealed that CEFIP overexpression further enhances calcineurin-dependent hypertrophic signal transduction, and its knockdown repressed hypertrophy and calcineurin/NFAT activity. In summary, we report on a previously uncharacterized protein CEFIP that modulates calcineurin/NFAT signaling in cardiomyocytes, a finding with possible implications for the pathogenesis of cardiomyopathy.
Keywords:
C10orf71; CEFIP; calcineurin; cardiac hypertrophy; cardiomyocyte; cardiomyopathy; cardiovascular disease; signaling; z-disc.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
MeSH terms
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Animals
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Animals, Newborn
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Calcineurin / metabolism*
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Cardiomegaly / metabolism
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Cardiomegaly / pathology
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line, Transformed
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Cells, Cultured
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Intercellular Signaling Peptides and Proteins
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LIM-Homeodomain Proteins / metabolism
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Mice
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Mice, Knockout
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Models, Biological*
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Muscle Fibers, Skeletal / cytology
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Muscle Fibers, Skeletal / metabolism*
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Muscle Fibers, Skeletal / pathology
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Muscle Proteins / antagonists & inhibitors
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Muscle Proteins / genetics
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Muscle Proteins / metabolism*
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / metabolism*
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Myocytes, Cardiac / pathology
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Protein Transport
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RNA Interference
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Rats, Wistar
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Recombinant Fusion Proteins / metabolism
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Sarcomeres / metabolism*
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Signal Transduction*
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Transcription Factors / metabolism
Substances
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C10orf71 protein, human
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Carrier Proteins
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Cefip protein, mouse
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Cefip protein, rat
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FHL2 protein, human
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Fhl2 protein, mouse
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Fhl2 protein, rat
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Intercellular Signaling Peptides and Proteins
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LIM-Homeodomain Proteins
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Muscle Proteins
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Recombinant Fusion Proteins
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Transcription Factors
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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Calcineurin