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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,1,8]]},"abstract":"<jats:p>\n                    Mutations in lysosomal-associated membrane protein 2 (\n                    <jats:italic>LAMP-2<\/jats:italic>\n                    ) 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\u2013lysosome fusion in human cardiomyocytes (CMs). Remarkably, LAMP-2B functions independently of syntaxin 17 (STX17), a protein that is essential for autophagosome\u2013lysosome 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\n                    <jats:italic>LAMP-2B<\/jats:italic>\n                    knockout in non-Danon hiPSC-CMs. Finally, gene correction of\n                    <jats:italic>LAMP-2<\/jats:italic>\n                    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\u2013mediated autophagy to treat this patient population.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1808618116","type":"journal-article","created":{"date-parts":[[2018,12,24]],"date-time":"2018-12-24T20:25:34Z","timestamp":1545683134000},"page":"556-565","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":130,"title":["LAMP-2B regulates human cardiomyocyte function by mediating autophagosome\u2013lysosome fusion"],"prefix":"10.1073","volume":"116","author":[{"given":"Congwu","family":"Chi","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Colorado Auschutz Medical Campus, Aurora, CO 80045;"},{"name":"Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Auschutz Medical Campus, Aurora, CO 80045;"},{"name":"The Consortium for Fibrosis Research &amp; Translation, University of Colorado Auschutz Medical Campus, Aurora, CO 80045;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Leonard","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, University of Washington, Seattle, WA 98195;"},{"name":"Center for Cardiovascular Biology, University of Washington, Seattle, WA 98195;"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter E.","family":"Knight","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Colorado Auschutz Medical Campus, Aurora, CO 80045;"},{"name":"Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Auschutz Medical Campus, Aurora, CO 80045;"},{"name":"The Consortium for Fibrosis Research &amp; Translation, University of Colorado Auschutz Medical Campus, Aurora, CO 80045;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin M.","family":"Beussman","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, University of Washington, Seattle, WA 98195;"},{"name":"Center for Cardiovascular Biology, University of Washington, Seattle, WA 98195;"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanbiao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Colorado Auschutz Medical Campus, Aurora, CO 80045;"},{"name":"Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Auschutz Medical Campus, Aurora, CO 80045;"},{"name":"The Consortium for Fibrosis Research &amp; 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