YAP plays a crucial role in the development of cardiomyopathy in lysosomal storage diseases

J Clin Invest. 2021 Mar 1;131(5):e143173. doi: 10.1172/JCI143173.


Lysosomal dysfunction caused by mutations in lysosomal genes results in lysosomal storage disorder (LSD), characterized by accumulation of damaged proteins and organelles in cells and functional abnormalities in major organs, including the heart, skeletal muscle, and liver. In LSD, autophagy is inhibited at the lysosomal degradation step and accumulation of autophagosomes is observed. Enlargement of the left ventricle (LV) and contractile dysfunction were observed in RagA/B cardiac-specific KO (cKO) mice, a mouse model of LSD in which lysosomal acidification is impaired irreversibly. YAP, a downstream effector of the Hippo pathway, was accumulated in RagA/B cKO mouse hearts. Inhibition of YAP ameliorated cardiac hypertrophy and contractile dysfunction and attenuated accumulation of autophagosomes without affecting lysosomal function, suggesting that YAP plays an important role in mediating cardiomyopathy in RagA/B cKO mice. Cardiomyopathy was also alleviated by downregulation of Atg7, an intervention to inhibit autophagy, whereas it was exacerbated by stimulation of autophagy. YAP physically interacted with transcription factor EB (TFEB), a master transcription factor that controls autophagic and lysosomal gene expression, thereby facilitating accumulation of autophagosomes without degradation. These results indicate that accumulation of YAP in the presence of LSD promotes cardiomyopathy by stimulating accumulation of autophagosomes through activation of TFEB.

Keywords: Autophagy; Cardiology; Signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cardiomyopathies / genetics
  • Cardiomyopathies / metabolism*
  • Cardiomyopathies / pathology
  • Hippo Signaling Pathway
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lysosomal Storage Diseases / genetics
  • Lysosomal Storage Diseases / metabolism*
  • Lysosomal Storage Diseases / pathology
  • Lysosomes / genetics
  • Lysosomes / metabolism
  • Lysosomes / pathology
  • Mice
  • Mice, Knockout
  • Monomeric GTP-Binding Proteins / deficiency
  • Monomeric GTP-Binding Proteins / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / metabolism*
  • Ventricular Dysfunction, Left / pathology
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • RagA protein, mouse
  • TFEB protein, human
  • TFEB protein, rat
  • Tcfeb protein, mouse
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Yap1 protein, mouse
  • Yap1 protein, rat
  • Protein Serine-Threonine Kinases
  • Monomeric GTP-Binding Proteins
  • RagB protein, mouse