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.
authors: Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92037, USA.
authors: Young Chul
authors: YC
authors: Kim
authors: Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92037, USA.
authors: Hyun Woo
authors: HW
authors: Park
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.|IRCCS Neuromed, Pozzilli (IS), Italy.
authors: Sebastiano
authors: S
authors: Sciarretta
authors: Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92037, USA.
authors: Jung-Soon
authors: JS
authors: Mo
authors: Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92037, USA.
authors: Jenna L
authors: JL
authors: Jewell
authors: Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92037, USA.
authors: Ryan C
authors: RC
authors: Russell
authors: Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai 200433, China.
authors: Xiaohui
authors: X
authors: Wu
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors: Junichi
authors: J
authors: Sadoshima
authors: Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92037, USA.
authors: Kun-Liang
authors: KL
authors: Guan
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D058570:TOR Serine-Threonine Kinases; C000589375:Rraga protein, Mouse; C000589376:Rragb protein, Mouse