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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >The ocular albinism type 1 (OA1) GPCR is ubiquitinated and its traffic requires endosomal sorting complex responsible for transport (ESCRT) function
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The ocular albinism type 1 (OA1) GPCR is ubiquitinated and its traffic requires endosomal sorting complex responsible for transport (ESCRT) function

机译：眼白化病1型（OA1）GPCR被泛素化其运输需要负责运输（ESCRT）功能的内体分选复合物

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The function of signaling receptors is tightly controlled by their intracellular trafficking. One major regulatory mechanism within the endo-lysosomal system required for receptor localization and down-regulation is protein modification by ubiquitination and downstream interactions with the endosomal sorting complex responsible for transport (ESCRT) machinery. Whether and how these mechanisms operate to regulate endosomal sorting of mammalian G protein-coupled receptors (GPCRs) remains unclear. Here, we explore the involvement of ubiquitin and ESCRTs in the trafficking of OA1, a pigment cell-specific GPCR, target of mutations in Ocular Albinism type 1, which localizes intracellularly to melanosomes to regulate their biogenesis. Using biochemical and morphological methods in combination with overexpression and inactivation approaches we show that OA1 is ubiquitinated and that its intracellular sorting and down-regulation requires functional ESCRT components. Depletion or overexpression of subunits of ESCRT-0, -I, and -III markedly inhibits OA1 degradation with concomitant retention within the modified endosomal system. Our data further show that OA1 ubiquitination is uniquely required for targeting to the intralumenal vesicles of multivesicular endosomes, thereby regulating the balance between down-regulation and delivery to melanosomes. This study highlights the role of ubiquitination and the ESCRT machinery in the intracellular trafficking of mammalian GPCRs and has implications for the physiopathology of ocular albinism type 1.
机译：信号受体的功能受到其细胞内运输的严格控制。受体定位和下调所需的溶酶体系统内的一种主要调节机制是通过泛素化和与负责运输（ESCRT）机制的内体分选复合物的下游相互作用来修饰蛋白质。这些机制是否起作用以及如何调节哺乳动物G蛋白偶联受体（GPCR）的内体分类尚不清楚。在这里，我们探讨了遍在蛋白和ESCRTs在OA1的运输中的参与，OA1是一种色素细胞特异性GPCR，是眼白化病1型突变的靶标，该病在细胞内定位于黑素体以调节其生物发生。使用生化和形态学方法结合过表达和失活方法，我们显示OA1遍在蛋白化，其细胞内分选和下调需要功能性ESCRT组件。 ESCRT-0，-I和-III亚基的耗竭或过表达显着抑制OA1降解，并同时保留在修饰的内体系统中。我们的数据进一步表明，OA1泛素化对于靶向多囊泡内体的腔内囊泡是唯一需要的，从而调节下调和向黑素体的递送之间的平衡。这项研究突出了泛素化和ESCRT机制在哺乳动物GPCR的细胞内运输中的作用，并对1型眼白化病的生理病理学具有影响。

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