RRC ID 47702
著者 Kimura H, Eguchi S, Sasaki J, Kuba K, Nakanishi H, Takasuga S, Yamazaki M, Goto A, Watanabe H, Itoh H, Imai Y, Suzuki A, Mizushima N, Sasaki T.
タイトル Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy.
ジャーナル JCI Insight
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.
巻・号 2(1)
ページ e89462
公開日 2017-1-12
DOI 10.1172/jci.insight.89462
PII 89462
PMID 28097232
PMC PMC5213877
MeSH Adult Aged Aged, 80 and over Animals Cardiomyopathy, Hypertrophic / genetics* Cardiomyopathy, Hypertrophic / metabolism Cardiomyopathy, Hypertrophic / prevention & control Class III Phosphatidylinositol 3-Kinases / genetics* Class III Phosphatidylinositol 3-Kinases / metabolism Death, Sudden, Cardiac Female Humans Male Mice Middle Aged Mutation / genetics Myofibrils / metabolism* Phosphorylation Prognosis Proteostasis / genetics* Ribosomal Protein S6 Kinases / metabolism TOR Serine-Threonine Kinases / metabolism alpha-Crystallin B Chain / genetics* alpha-Crystallin B Chain / metabolism
IF 6.205
引用数 12
リソース情報
ヒト・動物細胞 P19.CL6(RCB2318)