TY - JOUR
T1 - 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
AU - Shang, Peng
AU - Valapala, Mallika
AU - Grebe, Rhonda
AU - Hose, Stacey
AU - Ghosh, Sayan
AU - Bhutto, Imran A.
AU - Handa, James T.
AU - Lutty, Gerard A.
AU - Lu, Lixia
AU - Wan, Jun
AU - Qian, Jiang
AU - Sergeev, Yuri
AU - Puertollano, Rosa
AU - Zigler, J. Samuel
AU - Xu, Guo Tong
AU - Sinha, Debasish
N1 - Funding Information:
This study was funded by an unrestricted grant to the Wilmer Eye Institute from the Research to Prevent Blindness, National Eye Institute: EY019037-S (DS), EY019044 (JTH), EY14005 (JTH), EY01765 (Wilmer Imaging Core), and the National High Technology Research and Development Program of China (2013CB967501, 2015CB964601, 2013CB967101), Shanghai East Hospital (ZJ2014-2D-002), and Tongji Eye Institute (TEI-201403001). We thank Dr. Morton Goldberg for critical reading and discussions regarding this manuscript. We thank Drs. Ralph Nixon (CTSD), Donald Zack (Rhodopsin, M-opsin and PNAL), Krzysztof Palczewski (1D4), and T. Michael Redmond (RPE65) for the antibodies. DS is a guest professor at Tongji University School of Medicine, Shanghai, China, and a recipient of the Carolyn K. McGillvray Memorial Award for Macular Degeneration Research from BrightFocus Foundation, the Sybil B. Harrington Special Scholar Award for Macular Degeneration from Research to Prevent Blindness. JTH is the Robert Bond Welch Professor.
Publisher Copyright:
© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
KW - age-related macular degeneration
KW - amino acid transporter (PAT4/SLC36A4)
KW - complex 1 (mTORC1)
KW - coordinated lysosomal expression and regulation (CLEAR) network
KW - lysosomes; mechanistic target of rapamycin
KW - mouse model
KW - photoreceptor degeneration
KW - retinal pigmented epithelium (RPE)
KW - signal transduction
KW - transcription factors EB (TFEB) and E3 (TFE3)
KW - visual cycle proteins
UR - http://www.scopus.com/inward/record.url?scp=85009350192&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85009350192&partnerID=8YFLogxK
U2 - 10.1111/acel.12561
DO - 10.1111/acel.12561
M3 - Article
C2 - 28083894
AN - SCOPUS:85009350192
SN - 1474-9718
VL - 16
SP - 349
EP - 359
JO - Aging Cell
JF - Aging Cell
IS - 2
ER -