title: The amino acid transporter SLC36A4 regulates the amino acid pool in retinal pigmented epithelial cells and mediates the mechanistic target of rapamycin, complex 1 signaling.
abstract: The dry (nonneovascular) form of age-related macular degeneration (AMD), a leading cause of blindness in the elderly, has few, if any, treatment options at present. It is characterized by early accumulation of cellular waste products in the retinal pigmented epithelium (RPE); rejuvenating impaired lysosome function in RPE is a well-justified target for treatment. It is now clear that amino acids and vacuolar-type H+-ATPase (V-ATPase) regulate the mechanistic target of rapamycin, complex 1 (mTORC1) signaling in lysosomes. Here, we provide evidence for the first time that the amino acid transporter SLC36A4/proton-dependent amino acid transporter (PAT4) regulates the amino acid pool in the lysosomes of RPE. In Cryba1 (gene encoding βA3/A1-crystallin) KO (knockout) mice, where PAT4 and amino acid levels are increased in the RPE, the transcription factors EB (TFEB) and E3 (TFE3) are retained in the cytoplasm, even after 24 h of fasting. Consequently, genes in the coordinated lysosomal expression and regulation (CLEAR) network are not activated, and lysosomal function remains low. As these mice age, expression of RPE65 and lecithin retinol acyltransferase (LRAT), two vital visual cycle proteins, decreases in the RPE. A defective visual cycle would possibly slow down the regeneration of new photoreceptor outer segments (POS). Further, photoreceptor degeneration also becomes obvious during aging, reminiscent of human dry AMD disease. Electron microscopy shows basal laminar deposits in Bruch's membrane, a hallmark of development of AMD. For dry AMD patients, targeting PAT4/V-ATPase in the lysosomes of RPE cells may be an effective means of preventing or delaying disease progression.
authors.affiliation: Department of Ophthalmology of Shanghai Tenth People's Hospital and Laboratory of Clinical Visual Science of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China.|The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Shang
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Mallika
authors.initials: M
authors.lastname: Valapala
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Grebe
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Hose
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Sayan
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Imran A
authors.initials: IA
authors.lastname: Bhutto
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Handa
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Lutty
authors.affiliation: Department of Ophthalmology of Shanghai Tenth People's Hospital and Laboratory of Clinical Visual Science of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Lu
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wan
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sergeev
authors.affiliation: Cell Biology and Physiology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Puertollano
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: J Samuel
authors.initials: JS
authors.lastname: Zigler
authors.affiliation: Department of Ophthalmology of Shanghai Tenth People's Hospital and Laboratory of Clinical Visual Science of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China.|Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.|The Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, China.
authors.forename: Guo-Tong
authors.initials: GT
authors.lastname: Xu
authors.affiliation: The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Debasish
authors.initials: D
authors.lastname: Sinha
mesh_terms: D000375:Aging / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D003459:Crystallins / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D053263:Gene Regulatory Networks; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D055214:Retinal Photoreceptor Cell Outer Segment / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014795:Visual Pathways / Q000378:metabolism; D038205:beta-Crystallin A Chain
chemical_list: D026905:Amino Acid Transport Systems; D000596:Amino Acids; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C051374:Cryba1 protein, mouse; D003459:Crystallins; D046912:Multiprotein Complexes; C583919:PAT4 protein, mouse; C484068:Tcfeb protein, mouse; D038205:beta-Crystallin A Chain; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: age-related macular degeneration; amino acid transporter (PAT4/SLC36A4); complex 1 (mTORC1); coordinated lysosomal expression and regulation (CLEAR) network; lysosomes; mechanistic target of rapamycin; mouse model; photoreceptor degeneration; retinal pigmented epithelium (RPE); signal transduction; transcription factors EB (TFEB) and E3 (TFE3); visual cycle proteins