@article{3b13ca5a7435409392f780db9163fa9f,
title = "LAMP-2B regulates human cardiomyocyte function by mediating autophagosome–lysosome fusion",
abstract = "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.",
keywords = "Autophagosome–lysosome fusion, Autophagy, Cardiomyopathy, Danon disease, LAMP-2B",
author = "Congwu Chi and Andrea Leonard and Knight, {Walter E.} and Beussman, {Kevin M.} and Yuanbiao Zhao and Yingqiong Cao and Pilar Londono and Ellis Aune and Trembley, {Michael A.} and Small, {Eric M.} and Jeong, {Mark Y.} and Walker, {Lori A.} and Hongyan Xu and Sniadecki, {Nathan J.} and Taylor, {Matthew R.} and Buttrick, {Peter M.} and Kunhua Song",
note = "Funding Information: ACKNOWLEDGMENTS. This research was supported by funds from the Boettcher Foundation, American Heart Association Grant 13SDG17400031, the University of Colorado Department of Medicine Outstanding Early Career Scholar Program, and NIH Grant R01HL133230 (to K.S.). N.J.S. was supported by a National Science Foundation Grant CBET-1509106. A.L. was supported by an NIH postdoctoral fellowship (F32HL126332). W.E.K. was supported by a postdoctoral fellowship from the University of Colorado Consortium for Fibrosis Research & Translation and Cardiology training Grant T32HL007822. This research was also supported by Grants P30CA046934 and P30AR057212 and the Flow Cytometry, Genomics Shared Resources at the University of Colorado Anschutz Medical Campus. Funding Information: This research was supported by funds from the Boettcher Foundation, American Heart Association Grant 13SDG17400031, the University of Colorado Department of Medicine Outstanding Early Career Scholar Program, and NIH Grant R01HL133230 (to K.S.). N.J.S. was supported by a National Science Foundation Grant CBET-1509106. A.L. was supported by an NIH postdoctoral fellowship (F32HL126332). W.E.K. was supported by a postdoctoral fellowship from the University of Colorado Consortium for Fibrosis Research & Translation and Cardiology training Grant T32HL007822. This research was also supported by Grants P30CA046934 and P30AR057212 and the Flow Cytometry, Genomics Shared Resources at the University of Colorado Anschutz Medical Campus. Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All Rights Reserved.",
year = "2019",
month = jan,
day = "8",
doi = "10.1073/pnas.1808618116",
language = "English (US)",
volume = "116",
pages = "556--565",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "2",
}