Mutation in the βA3/A1-crystallin gene impairs phagosome degradation in the retinal pigmented epithelium of the rat
Mutation in the βA3/A1-crystallin gene impairs phagosome degradation in the retinal pigmented epithelium of the rat
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DOI：
10.1242/jcs.078790
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发表时间：
2011-02-15
影响因子：
4
通讯作者：
Sinha, Debasish
中科院分区：
文献类型：
--
作者：
Zigler, J. Samuel, Jr.;Zhang, Cheng;Sinha, Debasish
视网膜色素上皮（RPE）的主要功能是吞噬光感受器外节盘。我们首次证实晶状体的主要结构蛋白β A3/ a1 -晶体蛋白在RPE细胞中表达。此外，通过利用β A3/ a1结晶蛋白基因突变的Nuc1大鼠，我们发现RPE细胞需要这种蛋白来适当降解已被吞噬体内化的外节盘。我们还证明，在野生型RPE中，β A3/ a1结晶蛋白定位于溶酶体。然而，在Nuc1 RPE中，β A3/ a1结晶蛋白无法转运到溶酶体上，这可能是因为突变蛋白的错误折叠掩盖了适当运输所需的分选信号。被吞噬的外段的消化需要高水平的溶酶体酶活性，而在突变型RPE细胞中，负责外段蛋白质水解的主要酶组织蛋白酶D减少。有趣的是，我们的研究结果还表明，Nuc1 RPE中自噬过程存在缺陷，这可能也与溶酶体功能受损有关，因为吞噬作用和自噬在降解其靶标方面可能具有共同的机制。β A3/ a1 -晶体蛋白是RPE中一种新的溶酶体蛋白，对吞噬物质的降解至关重要。
Phagocytosis of the shed outer segment discs of photoreceptors is a major function of the retinal pigmented epithelium (RPE). We demonstrate for the first time that beta A3/A1-crystallin, a major structural protein of the ocular lens, is expressed in RPE cells. Further, by utilizing the Nuc1 rat, in which the beta A3/A1-crystallin gene is mutated, we show that this protein is required by RPE cells for proper degradation of outer segment discs that have been internalized in phagosomes. We also demonstrate that in wild-type RPE, beta A3/A1-crystallin is localized to the lysosomes. However, in the Nuc1 RPE, beta A3/A1-crystallin fails to translocate to the lysosomes, perhaps because misfolding of the mutant protein masks sorting signals required for proper trafficking. The digestion of phagocytized outer segments requires a high level of lysosomal enzyme activity, and cathepsin D, the major enzyme responsible for proteolysis of the outer segments, is decreased in mutant RPE cells. Interestingly, our results also indicate a defect in the autophagy process in the Nuc1 RPE, which is probably also linked to impaired lysosomal function, because phagocytosis and autophagy might share common mechanisms in degradation of their targets. beta A3/A1-crystallin is a novel lysosomal protein in RPE, essential for degradation of phagocytosed material.