c-Cbl-Dependent Monoubiquitination and Lysosomal Degradation of gp130

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.

ACKNOWLEDGMENTS

This work was supported in part by a grant-in-aid for Scientific Research from the Japan Society for the Promotion of Science, a grant-in-aid from the 21st Century Center of Excellence (COE) Program (Special Research Grant), a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture of the Japanese government, and a grant-in-aid from Daiwa Securities Health Foundation.

We are grateful to Mayumi Naramura (The University of Feinberg School of Medicine) and Hamid Band (Northwestern University) for c-Cbl null MEFs. We thank Masafumi Toyoshima for valuable discussions and Pejman Soroosh for critically reading the manuscript.