Rag GTPases are cardioprotective by regulating lysosomal function

Young Chul Kim, Hyun Woo Park, Sebastiano Sciarretta, Jung Soon Mo, Jenna L. Jewell, Ryan C. Russell, Xiaohui Wu, Junichi Sadoshima, Kun Liang Guan

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Abstract

The Rag family proteins are Ras-like small GTPases that have a critical role in amino-acid-stimulated mTORC1 activation by recruiting mTORC1 to lysosome. Despite progress in the mechanistic understanding of Rag GTPases in mTORC1 activation, little is known about the physiological function of Rag GTPases in vivo. Here we show that loss of RagA and RagB (RagA/B) in cardiomyocytes results in hypertrophic cardiomyopathy and phenocopies lysosomal storage diseases, although mTORC1 activity is not substantially impaired in vivo. We demonstrate that despite upregulation of lysosomal protein expression by constitutive activation of the transcription factor EB (TFEB) in RagA/B knockout mouse embryonic fibroblasts, lysosomal acidification is compromised owing to decreased v-ATPase level in the lysosome fraction. Our study uncovers RagA/B GTPases as key regulators of lysosomal function and cardiac protection.

Original languageEnglish
Article number4241
JournalNature communications
Volume5
DOIs
Publication statusPublished - 2014 Jul 1

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Kim, Y. C., Park, H. W., Sciarretta, S., Mo, J. S., Jewell, J. L., Russell, R. C., Wu, X., Sadoshima, J., & Guan, K. L. (2014). Rag GTPases are cardioprotective by regulating lysosomal function. Nature communications, 5, [4241]. https://doi.org/10.1038/ncomms5241