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

doi:10.1038/ncomms5241

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

Research output: Contribution to journal › Article › peer-review

67 Citations (Scopus)

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 language	English
Article number	4241
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5241
Publication status	Published - 2014 Jul 1

Bibliographical note

Funding Information:
We thank members of the Guan Lab for their discussions and especially thank Dr Masa Hoshijima (UCSD) for suggestions and examination of TEM data. We also thank Tracy Guo for her help and expertise on primary cardiomyocyte preparation, and we appreciate Dr Junghyun Bu’s help for the use of slide scanner. This work was supported by grants from the National Institutes of Health (CCT5042 and CCT2413) to K.-L.G.

All Science Journal Classification (ASJC) codes

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

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title = "Rag GTPases are cardioprotective by regulating lysosomal function",

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.",

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note = "Funding Information: We thank members of the Guan Lab for their discussions and especially thank Dr Masa Hoshijima (UCSD) for suggestions and examination of TEM data. We also thank Tracy Guo for her help and expertise on primary cardiomyocyte preparation, and we appreciate Dr Junghyun Bu{\textquoteright}s help for the use of slide scanner. This work was supported by grants from the National Institutes of Health (CCT5042 and CCT2413) to K.-L.G.",

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AU - Russell, Ryan C.

AU - Wu, Xiaohui

AU - Sadoshima, Junichi

AU - Guan, Kun Liang

N1 - Funding Information: We thank members of the Guan Lab for their discussions and especially thank Dr Masa Hoshijima (UCSD) for suggestions and examination of TEM data. We also thank Tracy Guo for her help and expertise on primary cardiomyocyte preparation, and we appreciate Dr Junghyun Bu’s help for the use of slide scanner. This work was supported by grants from the National Institutes of Health (CCT5042 and CCT2413) to K.-L.G.

PY - 2014/7/1

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N2 - 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.

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Rag GTPases are cardioprotective by regulating lysosomal function

Abstract

Bibliographical note

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