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First published online 29 April 2008
doi: 10.1242/jcs.024455

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Ubiquitin-independent binding of Hrs mediates endosomal sorting of the interleukin-2 receptor β-chain

Yuki Yamashita^1,*, Katsuhiko Kojima^1,*, Tomonori Tsukahara¹, Hideyuki Agawa¹, Koichiro Yamada¹, Yuji Amano¹, Naoki Kurotori¹, Nobuyuki Tanaka², Kazuo Sugamura³ and Toshikazu Takeshita^1,

¹ Department of Microbiology and Immunology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
² Division of Immunology, Miyagi Cancer Center Research Institute, Natori, Miyagi, 981-1293, Japan
³ Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

Author for correspondence (e-mail: takesit{at}shinshu-u.ac.jp)

Accepted 25 February 2008

Several lines of evidence have revealed that ubiquitylation of membrane proteins serves as a signal for endosomal sorting into lysosomes or lytic vacuoles. The hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) interacts with ubiquitylated cargoes through its ubiquitin-interacting-motif domain (UIM domain), and plays an essential early role in endosomal sorting. Here, we show that the C-terminal region of Hrs, which does not contain the UIM domain, can bind to interleukin-2 receptor β (IL-2Rβ). We found a direct interaction between bacterially expressed IL-2Rβ and Hrs in GST pull-down assays, indicating that their binding is independent of ubiquitin. Trafficking and degradation assays revealed that, similarly to wild-type IL-2Rβ, an IL-2Rβ mutant lacking all the cytoplasmic lysine residues is sorted from Hrs-positive early endosomes to LAMP1-positive late endosomes, resulting in degradation of the receptor. By contrast, an IL-2Rβ mutant lacking the Hrs-binding region passes through early endosomes and is mis-sorted to compartments positive for the transferrin receptor. The latter mutant exhibits attenuated degradation. Taken together, these results indicate that precise sorting of IL-2Rβ from early to late endosomes is mediated by Hrs, a known sorting component of the ubiquitin-dependent machinery, in a manner that is independent of UIM-ubiquitin binding.

Key words: IL-2Rβ, Hrs, Ubiquitin-dependent sorting