c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130.
Interleukin 6 (IL-6), a pleiotropic cytokine, functions in cells through its interaction with its receptor complex, which consists of two ligand-binding alpha 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.
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. tanaka-no735@pref.miyagi.jp
Yoshinori
Y
Tanaka
Nobuyuki
N
Tanaka
Yasushi
Y
Saeki
Keiji
K
Tanaka
Masaaki
M
Murakami
Toshio
T
Hirano
Naoto
N
Ishii
Kazuo
K
Sugamura
D000818:Animals; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000737:chemistry / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D018909:src Homology Domains
D056827:Endosomal Sorting Complexes Required for Transport; D015850:Interleukin-6; D010750:Phosphoproteins; D025801:Ubiquitin; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D050822:Cytokine Receptor gp130; D050721:Proto-Oncogene Proteins c-cbl; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D046988:Proteasome Endopeptidase Complex; D008239:Lysine