title: Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy.
abstract: Hypertrophic cardiomyopathy (HCM) is a common heart disease with a prevalence of 1 in 500 in the general population. Several mutations in genes encoding cardiac proteins have been found in HCM patients, but these changes do not predict occurrence or prognosis and the molecular mechanisms underlying HCM remain largely elusive. Here we show that cardiac expression of vacuolar protein sorting 34 (Vps34) is reduced in a subset of HCM patients. In a mouse model, muscle-specific loss of Vps34 led to HCM-like manifestations and sudden death. Vps34-deficient hearts exhibited abnormal histopathologies, including myofibrillar disarray and aggregates containing αB-crystallin (CryAB). These features result from a block in the ESCRT-mediated proteolysis that normally degrades K63-polyubiquitinated CryAB. CryAB deposition was also found in myocardial specimens from a subset of HCM patients whose hearts showed decreased Vps34. Our results identify disruption of the previously unknown Vps34-CryAB axis as a potentially novel etiology of HCM.
authors.affiliation: Research Center for Biosignaling, Department of.|Medical Biology.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Medical Biology.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Eguchi
authors.affiliation: Medical Biology.
authors.forename: Junko
authors.initials: J
authors.lastname: Sasaki
authors.affiliation: Biological Informatics and Experimental Therapeutics Pathology.
authors.forename: Keiji
authors.initials: K
authors.lastname: Kuba
authors.affiliation: Research Center for Biosignaling, Department of.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nakanishi
authors.affiliation: Medical Biology.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Takasuga
authors.affiliation: Cell Biology and Morphology.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Cellular and Organ Pathology, and.
authors.forename: Akiteru
authors.initials: A
authors.lastname: Goto
authors.affiliation: Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.affiliation: Biological Informatics and Experimental Therapeutics Pathology.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Department of Molecular Genetics, Division of Cancer Genetics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.affiliation: Research Center for Biosignaling, Department of.|Medical Biology.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D016757:Death, Sudden, Cardiac; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009210:Myofibrils / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D000074702:Proteostasis / Q000235:genetics*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000235:genetics* / Q000378:metabolism
chemical_list: C059215:CRYAB protein, human; D038203:alpha-Crystallin B Chain; C546842:MTOR protein, human; D058546:Class III Phosphatidylinositol 3-Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases