A hydrophobic amino acid cluster inserted into the C-terminus of a recycling cell surface receptor functions as an endosomal sorting signal
A hydrophobic amino acid cluster inserted into the C-terminus of a recycling cell surface receptor functions as an endosomal sorting signal
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DOI：
10.1016/j.bbrc.2013.10.019
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发表时间：
2013-11-08
影响因子：
3.1
通讯作者：
Takeshita, Toshikazu
中科院分区：
文献类型：
--
作者：
Amano, Yuji;Yoshino, Kazuhisa;Takeshita, Toshikazu
在配体刺激后泛素化的细胞表面受体被内化并递送至溶酶体途径进行降解。泛素化受体被ESCRT蛋白复合物捕获，将其分选到溶酶体途径。肝细胞生长因子调节的酪氨酸激酶底物（Hrs）是转运所需的内体分选复合物（ESCRT）-0的组分，其识别附着于受体的泛素，表明其作为泛素依赖性内体分选的关键分子起作用。在以前的白细胞介素（IL）-2受体β（IL-2 R β）和IL-4受体α（IL-4 R α）的研究中，它们在没有配体刺激的情况下组成性内化，我们揭示了Hrs以不依赖于泛素的方式与IL-2 R β和IL-4 R α结合，并鉴定了IL-2 R β和IL-4 R α胞质区域中的疏水氨基酸簇作为Hrs相互作用结构域。然而，含有插入到IL-2 R α的C-末端的疏水氨基酸簇的嵌合受体不被递送到晚期内体，而是再循环回到质膜。在本研究中，我们探索了与IL-2 R β中的内体分选相关的功能结构域以及疏水氨基酸簇，并发现了IL-2 R β中疏水氨基酸簇的C-末端之后的约30个氨基酸延伸的重要性。即使疏水氨基酸簇之后的氨基酸段由任意氨基酸组成，这样的段也允许分选能力，表明疏水氨基酸簇作为内体分选信号起作用。这些发现阐明了细胞因子受体的泛素非依赖性内体分选的分子机制的一部分，这些细胞因子受体在没有配体刺激的情况下组成性内化。(C)2013 Elsevier Inc. All rights reserved.
Cell surface receptors ubiquitylated after ligand stimulation are internalized and delivered to the lysosomal pathway for degradation. Ubiquitylated receptors are captured by ESCRT protein complexes that sort them to the lysosomal pathway. Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is a component of endosomal sorting complexes required for transport (ESCRT)-0 that recognizes ubiquitin attached to receptors, indicating that it functions as a key molecule for ubiquitin-dependent endosomal sorting. In a previous study on interleukin (IL)-2 receptor beta (IL-2R beta) and IL-4 receptor alpha (IL-4R alpha), which are constitutively internalized without ligand stimulation, we revealed that Hrs bound to IL-2R beta and IL-4R alpha in a ubiquitin-independent manner, and identified a hydrophobic amino acid cluster in the cytoplasmic region of IL-2R beta and IL-4R alpha as the Hrs-interacting domain. However, a chimeric receptor containing the hydrophobic amino acid cluster inserted into the C-terminal of IL-2R alpha was not delivered to late endosomes, but recycled back to the plasma membrane. In the present study, we explored the functional domain related to endosomal sorting in IL-2R beta together with the hydrophobic amino acid cluster, and discovered the importance of an approximately 30-amino acid stretch following the C-terminus of the hydrophobic amino acid cluster in IL-2R beta. Even though the amino acid stretch following the hydrophobic amino acid cluster was composed of arbitrary amino acids, such a stretch was also permissive for the sorting ability, suggesting that the hydrophobic amino acid cluster functions as an endosomal sorting signal. These findings clarify part of the molecular mechanism underlying the ubiquitin-independent endosomal sorting of cytokine receptors that are constitutively internalized without ligand stimulation. (C) 2013 Elsevier Inc. All rights reserved.