c-Cbl-Dependent Monoubiquitination and Lysosomal Degradation of gp130
c-Cbl-Dependent Monoubiquitination and Lysosomal Degradation of gp130
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DOI：
10.1128/mcb.01784-07
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发表时间：
2008-06
影响因子：
5.3
通讯作者：
Yoshinori Tanaka;N. Tanaka;Y. Saeki;Keiji Tanaka;M. Murakami;T. Hirano;N. Ishii;K. Sugamura
中科院分区：
文献类型：
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作者：
Yoshinori Tanaka;N. Tanaka;Y. Saeki;Keiji Tanaka;M. Murakami;T. Hirano;N. Ishii;K. Sugamura
白介素6(IL-6)是一种多效性细胞因子，通过与其受体复合体的相互作用发挥作用。受体复合体由两个配体结合的α亚基和两个信号转导亚基gp130组成。关于gp130介导的信号有大量的研究，但人们对其下调的了解较少。在这里，我们发现IL-6刺激诱导了gp130的溶酶体依赖的降解，这与gp130的K63连接的多泛素化增加相关。依赖刺激的gp130泛素化是由c-Cbl介导的，c-Cbl是一种E3连接酶，以酪氨酸磷酸化SHP2依赖的方式被招募到gp130。我们还发现，IL-6诱导gp130从细胞表面快速移位到内体隔室。此外，囊泡分选分子HRs通过直接识别其泛素化形式而促进了gp130的溶酶体降解。HRs或c-Cbl的缺失抑制了gp130的降解，从而导致IL-6信号的延长和放大。因此，我们的报告首次提供了c-Cb1/SHP2复合体参与IL-6刺激下gp130的泛素化和溶酶体降解的证据。Gp130的溶酶体降解是停止IL-6介导的信号转导的关键。
ABSTRACT Interleukin 6 (IL-6), a pleiotropic cytokine, functions in cells through its interaction with its receptor complex, which consists of two ligand-binding α subunits and two signal-transducing subunits known as gp130. There is a wealth of studies on signals mediated by gp130, but its downregulation is less well understood. Here we found that IL-6 stimulation induced lysosome-dependent degradation of gp130, which correlated with an increase in the K63-linked polyubiquitination of gp130. The stimulation-dependent ubiquitination of gp130 was mediated by c-Cbl, an E3 ligase, which was recruited to gp130 in a tyrosine-phosphorylated SHP2-dependent manner. We also found that IL-6 induced a rapid translocation of gp130 from the cell surface to endosomal compartments. Furthermore, the vesicular sorting molecule Hrs contributed to the lysosomal degradation of gp130 by directly recognizing its ubiquitinated form. Deficiency of either Hrs or c-Cbl suppressed gp130 degradation, which leads to a prolonged and amplified IL-6 signal. Thus, our present report provides the first evidence for involvement of a c-Cbl/SHP2 complex in ubiquitination and lysosomal degradation of gp130 upon IL-6 stimulation. The lysosomal degradation of gp130 is critical for cessation of IL-6-mediated signaling.