The novel cardiac z-disc protein CEFIP regulates cardiomyocyte hypertrophy by modulating calcineurin signaling

J Biol Chem. 2017 Sep 15;292(37):15180-15191. doi: 10.1074/jbc.M117.786764. Epub 2017 Jul 17.

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.

MeSH terms

  • Animals
  • Animals, Newborn
  • Calcineurin / metabolism*
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Transformed
  • Cells, Cultured
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • LIM-Homeodomain Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Models, Biological*
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle Fibers, Skeletal / pathology
  • Muscle Proteins / antagonists & inhibitors
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Protein Transport
  • RNA Interference
  • Rats, Wistar
  • Recombinant Fusion Proteins / metabolism
  • Sarcomeres / metabolism*
  • Signal Transduction*
  • Transcription Factors / metabolism

Substances

  • C10orf71 protein, human
  • Carrier Proteins
  • Cefip protein, mouse
  • Cefip protein, rat
  • FHL2 protein, human
  • Fhl2 protein, mouse
  • Fhl2 protein, rat
  • Intercellular Signaling Peptides and Proteins
  • LIM-Homeodomain Proteins
  • Muscle Proteins
  • Recombinant Fusion Proteins
  • Transcription Factors
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Calcineurin