Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting
Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting
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DOI：
10.1074/jbc.c100527200
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发表时间：
2001-12-07
影响因子：
4.8
通讯作者：
Benovic, JL
中科院分区：
文献类型：
--
作者：
Marchese, A;Benovic, JL
配体诱导的转运在许多G蛋白偶联受体(GPCRs)的生理调节中起着重要作用。尽管许多GPCR在长时间的刺激下被归类为降解途径，但导致降解的分子事件却鲜为人知。在这里，我们报告了人类免疫缺陷病毒辅助受体CXCR4经历了由激动剂促进的快速降解过程，该过程涉及通过笼蛋白包裹的凹坑进行内吞作用，并随后分选到溶酶体。对不同CXCR4突变体的分类研究表明，CXCR4的羧基末端存在一个降解基序(SSLKILSKGK)。前两个丝氨酸和二亮氨酸基序对于激动剂诱导的内吞作用是关键的，而所有三个丝氨酸而不是二亮氨酸在介导降解过程中起重要作用。3个赖氨酸残基突变对CXCR4内吞作用无影响，但完全抑制受体降解。由于赖氨酸残基代表泛素化的潜在位置，我们也研究了CXCR4的泛素化。有趣的是，CXCR4被证明经历了激动剂促进的快速泛素化，这种泛素化通过降解基序中赖氨酸残基的突变而减弱。这些研究表明，泛素化在将内吞的GPCRs分选到溶酶体中起着特定的作用。
Ligand-induced trafficking plays an important role in the physiologic regulation of many G protein-coupled receptors (GPCRs). Although numerous GPCRs are sorted to a degradative pathway upon prolonged stimulation, the molecular events leading to degradation are poorly understood. Here we report that the human immunodeficiency virus co-receptor CXCR4 undergoes rapid agonist-promoted degradation by a process involving endocytosis via clathrin-coated pits and subsequent sorting to lysosomes. Studies analyzing the sorting of various CXCR4 mutants revealed the presence of a degradation motif (SSLKILSKGK) in the carboxyl terminus of CXCR4. The first two serines as well as the dileucine motif were critical for agonist-induced endocytosis, whereas all three serines but not the dileucine were important in mediating degradation. Mutation of the three lysine residues had no effect on CXCR4 endocytosis yet completely inhibited receptor degradation. Because lysine residues represent potential sites of ubiquitination, we also examined the ubiquitination of CXCR4. Interestingly, CXCR4 was shown to undergo rapid agonist-promoted ubiquitination that was attenuated by mutation of the lysine residues within the degradation motif. These studies implicate a specific role for ubiquitination in sorting endocytosed GPCRs to lysosomes.