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 and Kun-Liang Guan ()
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Young Chul Kim: University of California at San Diego
Hyun Woo Park: University of California at San Diego
Sebastiano Sciarretta: Cardiovascular Research Institute, Rutgers New Jersey Medical School
Jung-Soon Mo: University of California at San Diego
Jenna L. Jewell: University of California at San Diego
Ryan C. Russell: University of California at San Diego
Xiaohui Wu: Institute of Developmental Biology and Molecular Medicine, Fudan University
Junichi Sadoshima: Cardiovascular Research Institute, Rutgers New Jersey Medical School
Kun-Liang Guan: University of California at San Diego

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5241

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