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First published online March 18, 2009
doi: 10.1242/10.1242/jcs.040055

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The E3 ubiquitin ligase LNX1p80 promotes the removal of claudins from tight junctions in MDCK cells

Senye Takahashi^1,*,, Noriko Iwamoto^1,2,*, Hiroyuki Sasaki³, Masato Ohashi⁴, Yukako Oda², Shoichiro Tsukita^1, and Mikio Furuse^2,¶

¹ Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501, Japan
² Division of Cell Biology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kusunoki-cho 7-5-1, Chuo-ku, Kobe 650-0017, Japan
³ Department of Molecular Cell Biology, Institute of DNA Medicine, The Jikei University School of Medicine, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan
⁴ Laboratory of Nano-Structure Physiology, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Higashiyama 5-1, Myodaiji-cho, Okazaki 444-8787, Japan

^¶ Author for correspondence (e-mail: furuse{at}med.kobe-u.ac.jp)

Accepted 27 November 2008

The structural continuity of tight junctions (TJs) is consistently maintained even when epithelial cells divide and move within the cellular sheet. This process is associated with dynamic remodeling of TJs by coordinated internalization and generation of claudin-based TJ strands, but the molecular mechanism behind the regulated turnover of TJs remains largely unknown. In this study, we identified the p80 isoform of the E3 ubiquitin ligase ligand of Numb-protein X1 (LNX1p80) as a protein binding to claudin-1. Interestingly, the concentration of claudins in TJs was remarkably reduced when LNX1p80 was overexpressed in MDCK cells, and there was a reduction not only in the number of TJ strands but also in the amount of detergent-insoluble claudins. We also found that LNX1p80 promoted polyubiquitylation of claudins. This ubiquitylation is dependent on its RING-finger domain and is not mediated by Lys48 of ubiquitin, which is used for protein degradation by the proteasome. Furthermore, LNX1p80 was often colocalized with claudins in vesicular structures containing markers for late endosomes and lysosomes. These findings suggest that LNX1p80 is involved in the ubiquitylation, endocytosis and lysosomal degradation of claudins, and that the turnover of TJs is regulated by ubiquitylation.

Key words: Tight junctions, Claudin, Ubiquitylation, LNX1, E3 ubiquitin ligase

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