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Molecular and Cellular Biology, August 2008, p. 4805-4818, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.01784-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

c-Cbl-Dependent Monoubiquitination and Lysosomal Degradation of gp130

Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan,¹ Division of Immunology, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan,² Laboratory of Frontier Science, Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan,³ Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan,⁴ Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan⁵

Received 28 September 2007/ Returned for modification 8 January 2008/ Accepted 17 May 2008

Interleukin 6 (IL-6), a pleiotropic cytokine, functions in cells through its interaction with its receptor complex, which consists of two ligand-binding 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.

Published ahead of print on 2 June 2008.