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Nat Commun. 2014 Jul 1;5:4241. doi: 10.1038/ncomms5241.

Rag GTPases are cardioprotective by regulating lysosomal function.

Author information

1
Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California 92037, USA.
2
1] Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California 92037, USA [2].
3
1] Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA [2] IRCCS Neuromed, Pozzilli (IS) 86077, Italy [3].
4
Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai 200433, China.
5
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.

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.

PMID:
24980141
PMCID:
PMC4100214
DOI:
10.1038/ncomms5241
[Indexed for MEDLINE]
Free PMC Article
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