Hrs Recognizes a Hydrophobic Amino Acid Cluster in Cytokine Receptors during Ubiquitin-independent Endosomal Sorting
Hrs Recognizes a Hydrophobic Amino Acid Cluster in Cytokine Receptors during Ubiquitin-independent Endosomal Sorting
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DOI：
10.1074/jbc.m110.191924
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发表时间：
2011-04-29
影响因子：
4.8
通讯作者：
Takeshita, Toshikazu
中科院分区：
文献类型：
--
作者：
Amano, Yuji;Yamashita, Yuki;Takeshita, Toshikazu
肝细胞生长因子调节的酪氨酸激酶底物（Hrs）是ESCRT-0蛋白复合物的一种组分，其捕获泛素化货物蛋白并将其分选到溶酶体途径。虽然Hrs作为一个关键的转运蛋白的泛素依赖性内体分选，我们以前报道，Hrs也参与了泛素不依赖性内体分选白细胞介素-2受体β（IL-2 R β）。在这里，我们显示了细菌表达的Hrs和白细胞介素-4受体α（IL-4 R α）之间的直接相互作用，表明它们的结合不是受体泛素化所必需的，类似于IL-2 R β的情况。对受体的Hrs结合区的检查揭示，IL-2 R β和IL-4 R α中的疏水氨基酸簇对于结合是必需的。而野生型受体被递送至LAMP 1阳性晚期内体，缺乏疏水性氨基酸簇的突变体受体被分选至溶血双磷脂酸阳性晚期内体而不是LAMP 1阳性晚期内体。我们还表明，这些突变体受体的降解减弱。因此，Hrs通过识别疏水氨基酸簇在受体的泛素非依赖性内体分选期间起作用。这些发现表明存在一组货物蛋白，其具有这种疏水氨基酸簇作为不依赖于泛素的分选信号。
Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is a component of the ESCRT-0 protein complex that captures ubiquitylated cargo proteins and sorts them to the lysosomal pathway. Although Hrs acts as a key transporter for ubiquitin-dependent endosomal sorting, we previously reported that Hrs is also involved in ubiquitin-independent endosomal sorting of interleukin-2 receptor beta (IL-2R beta). Here, we show direct interactions between bacterially expressed Hrs and interleukin-4 receptor alpha (IL-4R alpha), indicating that their binding is not required for ubiquitylation of the receptors, similar to the case for IL-2R beta. Examinations of the Hrs binding regions of the receptors reveal that a hydrophobic amino acid cluster in both IL-2R beta and IL-4R alpha is essential for the binding. Whereas the wild-type receptors are delivered to LAMP1-positive late endosomes, mutant receptors lacking the hydrophobic amino acid cluster are sorted to lysobisphosphatidic acid-positive late endosomes rather than LAMP1-positive late endosomes. We also show that the degradation of these mutant receptors is attenuated. Accordingly, Hrs functions during ubiquitin-independent endosomal sorting of the receptors by recognizing the hydrophobic amino acid cluster. These findings suggest the existence of a group of cargo proteins that have this hydrophobic amino acid cluster as a ubiquitin-independent sorting signal.