Lysosomal pool of free-amino acids

Harms, Erik; Gochman, Nathan; Schneider, Jerry A.

doi:10.1016/0006-291x(81)91239-0

Cited by 33 publications

(15 citation statements)

References 26 publications

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“…That V-ATPase can regulate the activation of MTORC1 in response to lysosomal amino acids has been demonstrated both in D. melanogaster and mammalian cells 14 . All essential amino acids are found to be concentrated within lysosomes 43 . The translocation of MTORC1 to the lysosomes is regulated by the multiprotein complex, Ragulator, which is an amino acid-regulated docking site for MTORC1 on lysosomes 26 .…”

Section: Discussionmentioning

confidence: 99%

Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/βA3/A1-crystallin via V-ATPase-MTORC1 signaling

et al. 2014

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In phagocytic cells, including the retinal pigment epithelium (RPE), acidic compartments of the endolysosomal system are regulators of both phagocytosis and autophagy, thereby helping to maintain cellular homeostasis. The acidification of the endolysosomal system is modulated by a proton pump, the V-ATPase, but the mechanisms that direct the activity of the V-ATPase remain elusive. We found that in RPE cells, CRYBA1/βA3/A1-crystallin, a lens protein also expressed in RPE, is localized to lysosomes, where it regulates endolysosomal acidification by modulating the V-ATPase, thereby controlling both phagocytosis and autophagy. We demonstrated that CRYBA1 coimmunoprecipitates with the ATP6V0A1/V0-ATPase a1 subunit. Interestingly, in mice when Cryba1 (the gene encoding both the βA3- and βA1-crystallin forms) is knocked out specifically in RPE, V-ATPase activity is decreased and lysosomal pH is elevated, while cathepsin D (CTSD) activity is decreased. Fundus photographs of these Cryba1 conditional knockout (cKO) mice showed scattered lesions by 4 months of age that increased in older mice, with accumulation of lipid-droplets as determined by immunohistochemistry. Transmission electron microscopy (TEM) of cryba1 cKO mice revealed vacuole-like structures with partially degraded cellular organelles, undigested photoreceptor outer segments and accumulation of autophagosomes. Further, following autophagy induction both in vivo and in vitro, phospho-AKT and phospho-RPTOR/Raptor decrease, while pMTOR increases in RPE cells, inhibiting autophagy and AKT-MTORC1 signaling. Impaired lysosomal clearance in the RPE of the cryba1 cKO mice also resulted in abnormalities in retinal function that increased with age, as demonstrated by electroretinography. Our findings suggest that loss of CRYBA1 causes lysosomal dysregulation leading to the impairment of both autophagy and phagocytosis.

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Section: Discussionmentioning

confidence: 99%

Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/βA3/A1-crystallin via V-ATPase-MTORC1 signaling

et al. 2014

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“…The yeast vacuole, organelle equivalent to mammalian lysosome, accumulates nutrients, such as AAs 64 , and the mechanism of mTORC1 recruitment is conserved in yeast 65 . In addition, high intraluminal concentrations of certain AAs have been shown also in lysosomes 66 . Protists such as D. dyscoideum obtain energy via phagocytosis and lysosomal degradation 67 , which is followed by a transient increase in intralysosomal nutrient levels.…”

Section: Amino Acid Sensingmentioning

confidence: 98%

Nutrient-sensing mechanisms and pathways

Efeyan

Comb

Sabatini

2015

Nature

916

794

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PREFACE The ability to sense and respond to fluctuations in environmental nutrient levels is a requisite for life. Nutrient scarcity is a selective pressure that has shaped the evolution of most cellular processes. Different pathways that detect intracellular and extracellular levels of sugars, amino acids and lipids, and surrogate metabolites, are then integrated and coordinated at the organismal level via hormonal signals. During food abundance, nutrient sensing pathways engage anabolism and storage, and scarcity triggers homeostatic mechanisms, like the mobilization of internal stores through mechanisms such as autophagy. Nutrient sensing pathways are commonly deregulated in human metabolic diseases.

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“…Given the preference of SLC38A9.1 for the transport of arginine and that arginine is highly concentrated in rat liver lysosomes (30) and yeast vacuoles (31), we asked whether SLC38A9.1 may have an important role in transmitting arginine levels to mTORC1. Towards this end we examined how mTORC1 signaling responded to a range of arginine or leucine concentrations in HEK-293T cells in which we knocked out SLC38A9 using CRISPR-Cas9 genome editing (Fig.…”

Section: Slc38a91 Is An Amino Acid Transportermentioning

confidence: 99%

Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1

Wang

Tsun

Wolfson

et al. 2015

Science

680

701

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The mTOR complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and v-ATPase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag GTPases and Ragulator in an amino acid-sensitive fashion. SLC38A9 transports arginine with a high Km and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is an excellent candidate for being an arginine sensor for the mTORC1 pathway.

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Lysosomal pool of free-amino acids

Cited by 33 publications

References 26 publications

Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/βA3/A1-crystallin via V-ATPase-MTORC1 signaling

Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/βA3/A1-crystallin via V-ATPase-MTORC1 signaling

Nutrient-sensing mechanisms and pathways

Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1

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