Arrestin-2 interacts with the ubiquitin-protein isopeptide ligase atrophin-interacting protein 4 and mediates endosomal sorting of the chemokine receptor CXCR4
Arrestin-2 interacts with the ubiquitin-protein isopeptide ligase atrophin-interacting protein 4 and mediates endosomal sorting of the chemokine receptor CXCR4
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DOI：
10.1074/jbc.m705085200
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发表时间：
2007-12-21
影响因子：
4.8
通讯作者：
Marchese, Adriano
中科院分区：
文献类型：
--
作者：
Bhandari, Deepali;Trejo, JoAnn;Marchese, Adriano
趋化因子受体CXCR4被E3泛素连接酶萎缩蛋白相互作用蛋白4 （AIP4）快速靶向溶酶体降解。虽然已知AIP4介导CXCR4的泛素化和降解，并且这些事件中的扰动有助于疾病，但介导AIP4依赖的CXCR4降解调节的机制仍然知之甚少。在这里，我们发现AIP4通过其WW结构域直接与非视觉抑制蛋白2的氨基末端相互作用。我们发现，通过小干扰RNA耗尽arrestin-2，通过阻止CXCR4从早期内体转运到溶酶体，阻断激动剂促进的CXCR4降解。令人惊讶的是，CXCR4的内化和泛素化保持不变，这表明抑制素-2和AIP4之间的相互作用不是质膜受体泛素化所必需的，但可能是内化后发生的事件。因此，我们发现CXCR4的激活促进AIP4和arrestin-2之间的相互作用，这与AIP4在内吞囊泡上与arrestin-2共定位的时间一致。综合来看，我们的数据表明AIP4。阻滞蛋白2复合物在核内体上调节CXCR4进入降解途径的分选。
The chemokine receptor CXCR4 is rapidly targeted for lysosomal degradation by the E3 ubiquitin ligase atrophin-interacting protein 4 (AIP4). Although it is known that AIP4 mediates ubiquitination and degradation of CXCR4 and that perturbations in these events contribute to disease, the mechanisms mediating AIP4-dependent regulation of CXCR4 degradation remain poorly understood. Here we show that AIP4 directly interacts with the amino-terminal half of nonvisual arrestin-2 via its WW domains. We show that depletion of arrestin-2 by small interfering RNA blocks agonist-promoted degradation of CXCR4 by preventing CXCR4 trafficking from early endosomes to lysosomes. Surprisingly, CXCR4 internalization and ubiquitination remain intact, suggesting that the interaction between arrestin-2 and AIP4 is not required for ubiquitination of the receptor at the plasma membrane but perhaps for a later post-internalization event. Accordingly, we show that activation of CXCR4 promotes the interaction between AIP4 and arrestin-2 that is consistent with a time when AIP4 co-localizes with arrestin-2 on endocytic vesicles. Taken together, our data suggest that the AIP4.arrestin-2 complex functions on endosomes to regulate sorting of CXCR4 into the degradative pathway.