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YAP/TFEB pathway promotes autophagic cell death and hypertrophic cardiomyopathy in lysosomal storage diseases
Inna Rabinovich-Nikitin, Lorrie A. Kirshenbaum
Inna Rabinovich-Nikitin, Lorrie A. Kirshenbaum
Published March 1, 2021
Citation Information: J Clin Invest. 2021;131(5):e146821. https://doi.org/10.1172/JCI146821.
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Commentary

YAP/TFEB pathway promotes autophagic cell death and hypertrophic cardiomyopathy in lysosomal storage diseases

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Abstract

Lysosomal storage disorders (LSD) are a group of inherited metabolic diseases characterized by lysosomal enzyme deficiency. The cardiac phenotype includes cardiomyopathy with eventual heart failure. Lysosome-mediated degradation processes, such as autophagy, maintain cellular homeostasis by discarding cellular debris and damaged organelles. Under stress, the transcription factor EB (TFEB) moves into the nucleus to activate transcription of lysosome biogenesis and autophagic proteins. In this issue of the JCI, Ikeda et al. report on their exploration of the signaling pathway involved with regulating lysosomal proteins specifically in the heart. The researchers generated a mouse model for LSD that was restricted to cardiac tissue. Unexpectedly, modulation of TFEB alone was insufficient to fully rescue the underlying clearance defect in lysosomal-associated disorders. The authors identified the Yes-associated protein (YAP)/TFEB signaling pathway as a key regulator of autophagosomes. These findings suggest that undigested autophagosomes accumulate and result in the cell death and cardiac dysfunction observed with LSD.

Authors

Inna Rabinovich-Nikitin, Lorrie A. Kirshenbaum

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Figure 1

Model for autophagy and lysosomal degradation in the regulation of LSD.

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Model for autophagy and lysosomal degradation in the regulation of LSD.
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During knockdown of RagA/B, YAP interacts with TFEB, causing accumulation of autophagosomes, decreased cardiac function, and enhanced cell death.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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