ALIX Regulates the Ubiquitin-Independent Lysosomal Sorting of the P2Y1 Purinergic Receptor via a YPX3L Motif.
ALIX Regulates the Ubiquitin-Independent Lysosomal Sorting of the P2Y1 Purinergic Receptor via a YPX3L Motif.
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DOI：
10.1371/journal.pone.0157587
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Trejo J
中科院分区：
文献类型：
--
作者：
Dores MR;Grimsey NJ;Mendez F;Trejo J
内吞分选和溶酶体降解是G蛋白偶联受体（GPCR）功能调节的组成部分。在配体结合后，经典的GPCR被激活、内化并再循环或分选到溶酶体中进行降解，这是一个需要受体泛素化的过程。然而，最近的研究表明，许多GPCR被分选到溶酶体独立的受体泛素化。在这里，我们描述了一个不依赖于泛素的嘌呤能GPCR P2 Y1的溶酶体分选途径。激活后，P2 Y1分选到溶酶体中进行降解，而不依赖于直接泛素化，直接泛素化由第二胞内环内的YPX 3L基序介导，该基序用作接头蛋白阿利克斯的结合位点。阿利克斯的耗尽或YPX 3L基序的定点突变抑制P2 Y1分选到多泡内体/溶酶体的腔中并降解。这些发现证实了YPX 3L基序作为GPCR的溶酶体靶向序列的功能，并证明阿利克斯介导某些GPCR的泛素非依赖性降解。
Endocytic sorting and lysosomal degradation are integral to the regulation of G protein-coupled receptor (GPCR) function. Upon ligand binding, classical GPCRs are activated, internalized and recycled or sorted to lysosomes for degradation, a process that requires receptor ubiquitination. However, recent studies have demonstrated that numerous GPCRs are sorted to lysosomes independent of receptor ubiquitination. Here, we describe an ubiquitin-independent lysosomal sorting pathway for the purinergic GPCR P2Y1. After activation, P2Y1 sorts to lysosomes for degradation independent of direct ubiquitination that is mediated by a YPX3L motif within the second intracellular loop that serves as a binding site for the adaptor protein ALIX. Depletion of ALIX or site-directed mutation of the YPX3L motif inhibits P2Y1 sorting into the lumen of multivesicular endosomes/lysosomes and degradation. These findings confirm the function of YPX3L motifs as lysosomal targeting sequences for GPCRs and demonstrate that ALIX mediates the ubiquitin-independent degradation of certain GPCRs.