期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 2, 页码 556-565出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1808618116
关键词
LAMP-2B; autophagy; cardiomyopathy; Danon disease; autophagosome-lysosome fusion
资金
- Boettcher Foundation
- American Heart Association [13SDG17400031]
- University of Colorado Department of Medicine Outstanding Early Career Scholar Program
- NIH [R01HL133230, F32HL126332]
- National Science Foundation [CBET-1509106]
- University of Colorado Consortium for Fibrosis Research & Translation and Cardiology training Grant [T32HL007822]
- Flow Cytometry, Genomics Shared Resources at the University of Colorado Anschutz Medical Campus
- [P30CA046934]
- [P30AR057212]
Mutations in lysosomal-associated membrane protein 2 (LAMP-2) gene are associated with Danon disease, which often leads to cardiomyopathy/heart failure through poorly defined mechanisms. Here, we identify the LAMP-2 isoform B (LAMP-2B) as required for autophagosome-lysosome fusion in human cardiomyocytes (CMs). Remarkably, LAMP-2B functions independently of syntaxin 17 (STX17), a protein that is essential for autophagosome-lysosome fusion in non-CMs. Instead, LAMP-2B interacts with autophagy related 14 (ATG14) and vesicle-associated membrane protein 8 (VAMP8) through its C-terminal coiled coil domain (CCD) to promote autophagic fusion. CMs derived from induced pluripotent stem cells (hiPSC-CMs) from Danon patients exhibit decreased colocalization between ATG14 and VAMP8, profound defects in autophagic fusion, as well as mitochondrial and contractile abnormalities. This phenotype was recapitulated by LAMP-2B knockout in non-Danon hiPSC-CMs. Finally, gene correction of LAMP-2 mutation rescues the Danon phenotype. These findings reveal a STX17-independent autophagic fusion mechanism in human CMs, providing an explanation for cardiomyopathy in Danon patients and a foundation for targeting defective LAMP-2B-mediated autophagy to treat this patient population.
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