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 T. Handa, Gerard A. Lutty, Lixia Lu, Jun Wan, Jiang Qian, Yuri Sergeev, Rosa Puertollano, J. Samuel Zigler, Guo Tong Xu, Debasish Sinha

Research output: Contribution to journalArticlepeer-review

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)
Pages (from-to)349-359
Number of pages11
JournalAging Cell
Volume16
Issue number2
DOIs
StatePublished - Apr 1 2017

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

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