Kim Young Chul, Park Hyun Woo, Sciarretta Sebastiano, Mo Jung-Soon, Jewell Jenna L, Russell Ryan C, Wu Xiaohui, Sadoshima Junichi, Guan Kun-Liang
Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92037, USA.
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
Nat Commun. 2014 Jul 1;5:4241. doi: 10.1038/ncomms5241.
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.
Rag家族蛋白是一类与Ras相似的小GTP酶，通过将mTORC1募集到溶酶体，在氨基酸刺激的mTORC1激活过程中发挥关键作用。尽管在Rag GTP酶激活mTORC1的机制理解方面取得了进展，但对于Rag GTP酶在体内的生理功能却知之甚少。在这里我们表明，心肌细胞中RagA和RagB（RagA/B）缺失会导致肥厚性心肌病，并模拟溶酶体贮积病，尽管在体内mTORC1活性并未受到实质性损害。我们证明，尽管在RagA/B基因敲除小鼠胚胎成纤维细胞中转录因子EB（TFEB）的组成性激活导致溶酶体蛋白表达上调，但由于溶酶体部分中v-ATP酶水平降低，溶酶体酸化受到损害。我们的研究揭示了RagA/B GTP酶是溶酶体功能和心脏保护的关键调节因子。
