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

Shohei Ikeda; Jihoon Nah; Akihiro Shirakabe; Peiyong Zhai; Shin-ichi Oka; Sebastiano Sciarretta; Kun-Liang Guan; Hiroaki Shimokawa; Junichi Sadoshima

doi:10.1172/JCI143173

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

Shohei Ikeda,¹ Jihoon Nah,² Akihiro Shirakabe,² Peiyong Zhai,² Shin-ichi Oka,² Sebastiano Sciarretta,³ Kun-Liang Guan,⁴ Hiroaki Shimokawa,¹ and Junichi Sadoshima²

Published December 29, 2020 - More info

View PDF

Abstract

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 knockout (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.

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

Shohei Ikeda,¹ Jihoon Nah,² Akihiro Shirakabe,² Peiyong Zhai,² Shin-ichi Oka,² Sebastiano Sciarretta,³ Kun-Liang Guan,⁴ Hiroaki Shimokawa,¹ and Junichi Sadoshima²

Article tools

Metrics

Go to

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

Shohei Ikeda,1 Jihoon Nah,2 Akihiro Shirakabe,2 Peiyong Zhai,2 Shin-ichi Oka,2 Sebastiano Sciarretta,3 Kun-Liang Guan,4 Hiroaki Shimokawa,1 and Junichi Sadoshima2

Article tools

Metrics

Go to

Sign up for email alerts

Shohei Ikeda,¹ Jihoon Nah,² Akihiro Shirakabe,² Peiyong Zhai,² Shin-ichi Oka,² Sebastiano Sciarretta,³ Kun-Liang Guan,⁴ Hiroaki Shimokawa,¹ and Junichi Sadoshima²