LAMP-2B regulates human cardiomyocyte function by mediating autophagosome–lysosome fusion

Congwu Chi, Andrea Leonard, Walter E. Knight, Kevin M. Beussman, Yuanbiao Zhao, Yingqiong Cao, Pilar Londono, Ellis Aune, Michael A. Trembley, Eric M. Small, Mark Y. Jeong, Lori A. Walker, Hongyan Xu, Nathan J. Sniadecki, Matthew R. Taylor, Peter M. Buttrick, Kunhua Song

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)556-565
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number2
DOIs
StatePublished - Jan 8 2019

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Lysosomal-Associated Membrane Protein 2
Cardiac Myocytes
Protein Isoforms
Induced Pluripotent Stem Cells
Autophagy
R-SNARE Proteins
Qa-SNARE Proteins
Cardiomyopathies
Glycogen Storage Disease Type IIb
Phenotype
Mutation
Genes
Heart Failure
Population

Keywords

  • Autophagosome–lysosome fusion
  • Autophagy
  • Cardiomyopathy
  • Danon disease
  • LAMP-2B

ASJC Scopus subject areas

  • General

Cite this

LAMP-2B regulates human cardiomyocyte function by mediating autophagosome–lysosome fusion. / Chi, Congwu; Leonard, Andrea; Knight, Walter E.; Beussman, Kevin M.; Zhao, Yuanbiao; Cao, Yingqiong; Londono, Pilar; Aune, Ellis; Trembley, Michael A.; Small, Eric M.; Jeong, Mark Y.; Walker, Lori A.; Xu, Hongyan; Sniadecki, Nathan J.; Taylor, Matthew R.; Buttrick, Peter M.; Song, Kunhua.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 2, 08.01.2019, p. 556-565.

Research output: Contribution to journalArticle

Chi, C, Leonard, A, Knight, WE, Beussman, KM, Zhao, Y, Cao, Y, Londono, P, Aune, E, Trembley, MA, Small, EM, Jeong, MY, Walker, LA, Xu, H, Sniadecki, NJ, Taylor, MR, Buttrick, PM & Song, K 2019, 'LAMP-2B regulates human cardiomyocyte function by mediating autophagosome–lysosome fusion', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 2, pp. 556-565. https://doi.org/10.1073/pnas.1808618116
Chi, Congwu ; Leonard, Andrea ; Knight, Walter E. ; Beussman, Kevin M. ; Zhao, Yuanbiao ; Cao, Yingqiong ; Londono, Pilar ; Aune, Ellis ; Trembley, Michael A. ; Small, Eric M. ; Jeong, Mark Y. ; Walker, Lori A. ; Xu, Hongyan ; Sniadecki, Nathan J. ; Taylor, Matthew R. ; Buttrick, Peter M. ; Song, Kunhua. / LAMP-2B regulates human cardiomyocyte function by mediating autophagosome–lysosome fusion. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 2. pp. 556-565.
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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.",
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AU - Leonard, Andrea

AU - Knight, Walter E.

AU - Beussman, Kevin M.

AU - Zhao, Yuanbiao

AU - Cao, Yingqiong

AU - Londono, Pilar

AU - Aune, Ellis

AU - Trembley, Michael A.

AU - Small, Eric M.

AU - Jeong, Mark Y.

AU - Walker, Lori A.

AU - Xu, Hongyan

AU - Sniadecki, Nathan J.

AU - Taylor, Matthew R.

AU - Buttrick, Peter M.

AU - Song, Kunhua

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