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.
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.
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DOI：
10.1111/acel.12561
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发表时间：
2017-04
期刊：
影响因子：
7.8
通讯作者：
Sinha D
中科院分区：
文献类型：
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作者：
Shang P;Valapala M;Grebe R;Hose S;Ghosh S;Bhutto IA;Handa JT;Lutty GA;Lu L;Wan J;Qian J;Sergeev Y;Puertollano R;Zigler JS Jr;Xu GT;Sinha D
干性(非新生血管性)老年性黄斑变性(AMD)是老年人失明的主要原因，目前几乎没有治疗选择。它的特点是细胞废物在视网膜色素上皮(RPE)早期积聚；恢复RPE受损的溶酶体功能是一个很好的治疗目标。目前已清楚的是，氨基酸和液泡型H+-ATPase(V-ATPase)调节溶酶体中雷帕霉素复合体1(MTORC1)信号的机制靶点。在这里，我们首次提供了氨基酸转运蛋白SLC36A4/质子依赖氨基酸转运蛋白(PAT4)调节RPE溶酶体中氨基酸库的证据。在Cryba1(编码βA3/A1-晶体蛋白的基因)KO(基因敲除)小鼠中，RPE中的PAT4和氨基酸水平增加，即使在禁食24小时后，转录因子EB(TFEB)和E3(TFE3)仍保留在细胞质中。因此，协调溶酶体表达和调节(CLEAR)网络中的基因没有被激活，溶酶体功能仍然很低。随着这些小鼠年龄的增长，RPE中两种重要的视觉周期蛋白RPE65和卵磷脂视黄醇酰基转移酶(LRAT)的表达减少。视觉周期缺陷可能会减慢新的光感受器外节(POS)的再生。此外，随着年龄的增长，光感受器退化也变得明显，这让人想起人类干性AMD疾病。电子显微镜下可见Bruch膜上的基底层沉积，这是AMD发生的标志。对于干性AMD患者，靶向RPE细胞溶酶体中的PAT4/V-ATPase可能是预防或延缓疾病进展的有效手段。
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.