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Photo Cell Biology & Biochemistry Laboratory
BAG6 (also known as BAT3/Scythe) is a ubiquitin-like protein that is thought to participate in a variety of seemingly unrelated physiological and pathological processes, such as apoptosis, antigen presentation and the T cell response. Recent studies have shown that BAG6 is essential for the quality control of aggregation-prone polypeptide biogenesis. It forms part of a complex that determines the fate of newly synthesized client proteins for membrane insertion, ubiquitin-mediated degradation and/or aggregate formation. A biologically relevant transmembrane protein family has recently been shown to be a major client of BAG6, suggesting that many of the known diverse BAG6 functions can be interpreted by BAG6-mediated control of membrane protein biogenesis. We are intrested in the physiological roles of BAG6 with a particular focus on quality control for newly-synthesized transmembrane proteins.

Otani group is interested in cell-cell junctions and epithelial homeostasis. We study how cell junctions are made, maintained, and are developing tools to manipulate cell-cell junctions.
Faculty
Prof Hiroyuki Kawahara e-mail
Asc Prof Tetsuhisa Otani e-mail
Ast Prof Naoto Yokota e-mail
Recent Publications
  1. Hagiwara, T., Minami, R., Ushio, C., Yokota, N., and Kawahara, H. (2023) Proteotoxic stresses stimulates dissociation of UBL4A from the tail-anchored protein recognition complex. Biochem. J. (London), doi: 10.1042/BCJ20230267
  2. Takahashi, T., Shirai, J., Matsuda, M., Nakanaga, S., Matsushita, S., Wakita, K., Hayashishita, M., Suzuki, R., Noguchi, A., Yokota, N., and Kawahara, H. (2023) Protein quality control machinery supports primary ciliogenesis by eliminating GDP-bound Rab8-family GTPases.iScience, 26:doi.org/10.1016/j.isci.2023.106652
  3. Miyauchi, M., Matsumura, R., and Kawahara, H. (2023) BAG6 supports stress fiber formation by preventing the ubiquitin-mediated degradation of RhoA.
  4. Matsuura, Y., Noguchi, A., Yokota, N., and Kawahara, H. (2020) Nuclear accumulation of ZFP36L1 is cell cycle-dependent and determined by a C-terminal serine-rich cluster.J. Biochem. 168, 477-489.
  5. Mimami, S., Yokota, N., and Kawahara, H. (2020) BAG6 contributes glucose uptake by supporting the cell surface translocation of the glucose transporter GLUT4. Biol. Open. 9, bio047324.
  6. Takahashi, T., Minami, S., Tajima, K., Tsuchiya, Y., Sakai, N., Suga, K., Hisanaga, S., Obayashi, N., Fukuda, M., and Kawahara, H. (2019) Cytoplasmic control of Rab-family small GTPases through BAG6.EMBO Rep. 20: e46794.
  7. Kamikubo, K., Kato, H., Kioka, H., Yamazaki, S., Tsukamoto, O., Nishida, Y., Asano, Y., Imamura, H., Kawahara, H., Shintani, Y., and Takashima, S. (2019) A molecular triage process mediated by RING finger protein 126 and BCL2-associated athanogene 6 regulates degradation of G0/G1 switch gene 2. J. Biol. Chem. 294, 14562-14573.
  8. Hayashishita, M., Kawahara, H., and Yokota N. (2019) BAG6 deficiency induces mis-distribution of mitochondrial clusters under depolarization. FEBS Open Bio. 9, 1281-1291.
  9. Demizu, S., Asaka, M., Kawahara, H. and Sasaki, E. (2019) TAS-203, an oral phosphodiesterase 4 inhibitor, suppresses goblet cell hyperplasia and MUC5AC production in rodent models. Eur. J. Pharmacol. 849, 22-29.
  10. Noguchi, A., Adachi, S., Yokota, N., Hatta, T., Natsume, T., and Kawahara, H. (2018) ZFP36L2 is a cell cycle-regulated CCCH-protein necessary for DNA lesion-induced S-phase arrest. Biol. Open 7, bio031575.
  11. Kondo, M., Noguchi, A., Matsuura, Y., Shimada, M., Yokota, N., and Kawahara, H. (2018) Novel phosphorelay-dependent control of ZFP36L1 protein during the cell cycle. Biochem. Biophys. Res. Comm. 501; 387-393.
  12. Xuan, X., Matsumoto, S., Endo, S., Fukushima, A., Kawahara, H., Saeki, Y., and Komada, M. (2018) Deubiquitinases USP5 and USP13 are recruited to and regulate heat-induced stress granules by deubiquitinating activities. J. Cell Sci. 131, 1-11. doi: 10.1242/jcs.210856.
  13. Yamamoto, K., Hayashishita, M., Minami, S., Suzuki, K., Hagiwara, T., Noguchi, A., and Kawahara, H. (2017) Elimination of a signal-sequence uncleaved form of defective HLA protein through BAG6. Sci. Rep. 7, DOI:10.1038/s41598-017-14975-9
  14. Suzuki, R. and Kawahara, H. (2016) UBQLN4 recognizes mislocalized transmembrane domain proteins and targets these to proteasomal degradation. EMBO Rep. 17, 842–857.
  15. Tanaka, H., Takahashi, T., Xie, Y., Minami, R., Yanagi, Y., Hayashishita, M., Suzuki, R., Yokota, N., Shimada, M., Mizushima, T., Kuwabara, N., Kato, R., and Kawahara, H. (2016) A conserved island of BAG6/Scythe is related to ubiquitin domains and participates in short hydrophobicity recognition. FEBS J. 283, 662–677.
  16. Takasugi, T., Saito, T., Asada, A., Kawahara, H. and Hisanaga, S.-I. (2016) Two degradation pathways of the p35 Cdk5 activation subunit, dependent and independent of ubiquitination. J. Biol. Chem. 291, 4649-4657. doi: 10.1074/jbc.M115.692871
  17. Yamaki, Y., Kagawa, H., Hatta, T., Natsume, T., and Kawahara, H. (2016) The C-terminal cytoplasmic tail of hedgehog receptor Patched1 is a platform for E3 ubiquitin ligase complexes. Mol. Cell. Biochem. 414: 1-12.
  18. Kuwabara, N., Minami, R., Yokota, N., Matsumoto, H., Senda, T., Kawahara, H. (co-corresponding author), and Kato, R. (2015) Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (ubiquitin-like protein 4a) complex reveals a novel binding interface that functions in tail-anchored protein biogenesis. J. Biol. Chem. 290, 9387-9398.
  19. Kawahara, H., Minami, R. and Yokota, N. (2013) JB Review: BAG6/BAT3: Emerging roles in quality control for nascent polypeptides. J. Biochem. 153, 147-160.
  20. Kagawa, H., Shino, Y., Kobayashi, D., Demizu, S., Shimada. M., Ariga, H. and Kawahara, H. (2011) A novel signaling pathway mediated by the nuclear targeting of C-terminal fragments of mammalian Patched 1. PLoS ONE @6: e18638.
  21. Sato, K., Minegishi, S., Takano, J., Plattner, F., Saito, T., Asada, A., Kawahara, H., Iwata, N., Saido, T.C., and Hisanaga, S. (2011) Calpastatin, an endogenous calpain-inhibitor protein, regulates the cleavage of the Cdk5 activator p35 to p25. J. Neurochem. 117:504-515.
  22. Minami, R., Hayakawa, A., Kagawa, H., Yanagi, Y., Yokosawa, H. and Kawahara, H. (2010) BAG-6 is essential for selective elimination of defective proteasomal substrates. J. Cell Biol. 190: 637-650.
  23. Ojima, K., Y Kawabata, Y., Nakao, H., Nakao, K., Doi, N., Kitamura, F., Ono, Y., Hata, S., Suzuki, H., Kawahara, H., Labeit, S., Toyama-Sorimachi, N., Suzuki, K., Maeda, T., Abe, K., Aiba, A., and Sorimachi, H. (2010) Role of dynamic distribution of muscle-specific calpain in physical-stress adaptation and muscular dystrophy in mice. J. Clin. Invest. 120: 2672–2683.
  24. Shimada, M., Kanematsu, K., Tanaka, K., Yokosawa, H. and Kawahara, H. (2006) Proteasomal ubiquitin receptor RPN-10 controls sex determination in Caenorhabditis elegans. Mol. Biol. Cell 17: 5356-5371.
  26. Tight junction membrane proteins regulate the mechanical resistance of the apical junctional complex. TP Nguyen, T Otani*, M Tsutsumi, N Kinoshita, S Fujiwara, T Nemoto, T Fujimori, M Furuse*. Journal of Cell Biology 223 (5), e202307104, (2024)
  27. ​Mechanism of interdigitation formation at apical boundary of MDCK cell. S Miyazaki, T Otani, K Sugihara, T Fujimori, M Furuse, T Miura. iScience 26 (5), 106594. (2023)
  28. Tight junction formation by a claudin mutant lacking the COOH]terminal PDZ domain]binding motif. S Fujiwara, TP Nguyen, K Furuse, Y Fukazawa, T Otani, M Furuse. Annals of the New York Academy of Sciences 1516 (1), 85-94. (2022)
  29. Angulin-1 seals tricellular contacts independently of tricellulin and claudins. T Sugawara, K Furuse, T Otani, T Wakayama, M Furuse. Journal of Cell Biology 220 (9), e202005062. (2021)
  30. Occludin and tricellulin facilitate formation of anastomosing tight-junction strand network to improve barrier function. AC Saito, T Higashi, Y Fukazawa, T Otani, M Tauchi, AY Higashi, M Furuse, H Chiba. Molecular biology of the cell 32 (8), 722-738. (2021)
  31. Tight junction structure and function revisited. T Otani*, M Furuse. Trends in cell biology 30 (10), 805-817. (2020)
  32. Claudins and JAM-A coordinately regulate tight junction formation and epithelial polarity. T Otani, TP Nguyen, S Tokuda, K Sugihara, T Sugawara, K Furuse, T Miura, K Ebnet, M Furuse. Journal of Cell Biology 218 (10), 3372-3396. (2019)
©2015 Department of Biological Sciences, Tokyo Metropolitan University