title: JunB-CBFbeta signaling is essential to maintain sarcomeric Z-disc structure and when defective leads to heart failure.
abstract: In muscle cells, a complex network of Z-disc proteins allows proper reception, transduction and transmission of mechanical and biochemical signals. Mutations in genes encoding different Z-disc proteins such as integrin-linked kinase (ILK) and nexilin have recently been shown to cause heart failure by distinct mechanisms such as disturbed mechanosensing, altered mechanotransduction or mechanical Z-disc destabilization. We identified core-binding factor β (CBFβ) as an essential component for maintaining sarcomeric Z-disc and myofilament organization in heart and skeletal muscle. In CBFβ-deficient cardiomyocytes and skeletal-muscle cells, myofilaments are thinned and Z-discs are misaligned, leading to progressive impairment of heart and skeletal-muscle function. Transcription of the gene encoding CBFβ mainly depends on JunB activity. In JunB-morphant zebrafish, which show a heart-failure phenotype similar to that of CBFβ-deficient zebrafish, transcript and protein levels of CBFβ are severely reduced. Accordingly, ectopic expression of CBFβ can reconstitute cardiomyocyte function and rescue heart failure in JunB morphants, demonstrating for the first time an essential role of JunB-CBFβ signaling for maintaining sarcomere architecture and function.
authors.affiliation: Department of Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.forename: Britta
authors.initials: B
authors.lastname: Vogel
authors.forename: Jessica
authors.initials: J
authors.lastname: Rudloff
authors.forename: Linda
authors.initials: L
authors.lastname: Gärtner
authors.forename: Tillman
authors.initials: T
authors.lastname: Dahme
authors.forename: Inken
authors.initials: I
authors.lastname: Huttner
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zankl
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D050658:Core Binding Factor beta Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism; D016133:Polymerase Chain Reaction; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D012518:Sarcomeres / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014463:Ultrasonography; D015027:Zebrafish
chemical_list: D050658:Core Binding Factor beta Subunit; D016755:Proto-Oncogene Proteins c-jun