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

Peng Shang, Mallika Valapala, Rhonda Grebe, Stacey Hose, Sayan Ghosh, Imran A. Bhutto, James Handa, Gerard Anthony Lutty, Lixia Lu, Jun Wan, Jiang Qian, Yuri Sergeev, Rosa Puertollano, J. Samuel Zigler, Guo Tong Xu, Debasish Sinha

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalAging Cell
DOIs
StateAccepted/In press - 2017

Fingerprint

Amino Acid Transport Systems
Epithelium
Epithelial Cells
Macular Degeneration
Lysosomes
Amino Acids
Vacuolar Proton-Translocating ATPases
Bruch Membrane
Waste Products
Crystallins
Blindness
Knockout Mice
Genes
Disease Progression
mechanistic target of rapamycin complex 1
Protons
Regeneration
Fasting
Electron Microscopy
Cytoplasm

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

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

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. / Shang, Peng; Valapala, Mallika; Grebe, Rhonda; Hose, Stacey; Ghosh, Sayan; Bhutto, Imran A.; Handa, James; Lutty, Gerard Anthony; Lu, Lixia; Wan, Jun; Qian, Jiang; Sergeev, Yuri; Puertollano, Rosa; Zigler, J. Samuel; Xu, Guo Tong; Sinha, Debasish.

In: Aging Cell, 2017.

Research output: Contribution to journalArticle

Shang, Peng ; Valapala, Mallika ; Grebe, Rhonda ; Hose, Stacey ; Ghosh, Sayan ; Bhutto, Imran A. ; Handa, James ; Lutty, Gerard Anthony ; Lu, Lixia ; Wan, Jun ; Qian, Jiang ; Sergeev, Yuri ; Puertollano, Rosa ; Zigler, J. Samuel ; Xu, Guo Tong ; Sinha, Debasish. / 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. In: Aging Cell. 2017.
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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.",
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author = "Peng Shang and Mallika Valapala and Rhonda Grebe and Stacey Hose and Sayan Ghosh and Bhutto, {Imran A.} and James Handa and Lutty, {Gerard Anthony} and Lixia Lu and Jun Wan and Jiang Qian and Yuri Sergeev and Rosa Puertollano and Zigler, {J. Samuel} and Xu, {Guo Tong} and Debasish Sinha",
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AU - Shang, Peng

AU - Valapala, Mallika

AU - Grebe, Rhonda

AU - Hose, Stacey

AU - Ghosh, Sayan

AU - Bhutto, Imran A.

AU - Handa, James

AU - Lutty, Gerard Anthony

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

PY - 2017

Y1 - 2017

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.

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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

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