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Department of Biological Sciences
Molecular Neuroscience
Developmental Biology
Cellular Genetics
Molecular Genetics
Plant Development and Physiology
Cellular Biochemistry
Evolutionary Genetics
Plant Environmental Responses
Environmental Microbiology
Animal Ecology
Plant Ecology
Systematic Zoology
Systematic Botany
Photosynthetic Microbial Consortia
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.
Prof Hiroyuki Kawahara e-mail
Ast Prof Naoto Yokota e-mail
Recent Publications
  1. 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. in press
  2. 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. in press
  3. 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, doi: 10.1242/bio.031575
  4. Kondo, M., Noguchi, A., Matsuura, Y., Shimada, M., Yokota, N., Kawahara, H. (2018) Novel phosphorelay-dependent control of ZFP36L1 protein during the cell cycle. Biochem. Biophys. Res. Comm. 501, 387-393.
  5. 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, doi: 10.1242/jcs.210856
  6. Yamamoto, K., Hayashishita, M., Minami, S., Suzuki, K., Hagiwara, T., Noguchi, A., and Kawahara, H. (2017) Elimination of a signal-sequence uncleaved form of mislocalized HLA protein through BAG6. Sci. Rep. in press
  7. Suzuki, R. and Kawahara, H. (2016) UBQLN4 recognizes mislocalized transmembrane domain proteins and targets these to proteasomal degradation. EMBO Rep. 17, Published online April 22, 2016, DOI 10.15252/embr.201541402
  8. 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. DOI: 10.1111/febs.13618
  9. Takasugi, T., Minegishi, S., Asada, A., Saito, T., 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
  10. 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. DOI: 10.1007/s11010-015-2643-4
  11. Kuwabara, N., Minami, R., Yokota, N., Matsumoto, H., Senda, T., Kawahara, H., and Kato, R. (2015) Structure of a BAG6–Ubl4a complex reveals a novel binding interface that functions in tail-anchored protein biogenesis. J. Biol. Chem. 290, 9387-9398.
  12. 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.
  13. 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. doi:10.1371/journal.pone.0018638
  14. 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.
  15. Yokota, N., Kataoka, Y., Hashii, N., Kawasaki, N., and Sawada, H. (2011) Sperm-specific C-terminal processing of the proteasome PSMA1/6 subunit. Biochem. Biophys. Res. Commun. 410:809-815
  16. 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.
  17. 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. Clinc. Invest. 120: 2672|2683.
  18. Endo, R., Saito, T., Asada, A., Kawahara, H. and Hisanaga, S.-I. (2009) Commitment of 1-methyl-4-phenylpyrinidinium ion-induced neuronal cell death by proteasome-mediated degradation of p35 Cyclin-dependent kinase 5 activator. J. Biol. Chem. 284, 26029-26039.
  19. Minami, R., Shimada, M., Yokosawa, H. and Kawahara, H. (2007) Scythe regulates apoptosis through modulating ubiquitin-mediated proteolysis of XEF1AO. Biochem. J. (London) 405: 495-501.
  20. Hamazaki, J., Sasaki, K., Kawahara, H., Hisanaga, S., Tanaka, K., and Murata, S. (2007) Rpn10-mediated degradation of ubiquitinated proteins is essential for mouse development. Mol. Cell. Biol. 27: 5529-6638.
  21. Tayama, Y., Kawahara, H., Minami, R., Shimada, M., and Yokosawa, H. (2007) Association of Rpn10 with high molecular weight complex is enhanced during retinoic acid-induced differentiation of neuroblastoma cells. Mol. Cell. Biochem.
  22. 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.
  23. Shimada, M., Yokosawa, H., and Kawahara, H. (2006) OMA-1 is a P granules-associated protein that is required for germline specification in C. elegans. Genes Cells 11, 383-396.
  24. Hata, S., Koyama, S., Kawahara, H., Doi, N., Maeda, T., Toyama-Sorimachi, N., Abe, K., Suzuki, K., and Sorimachi, H. (2006) Stomach-specific calpain localizes in mucus cells and proteolyses the -subunit of coatomer complex, -COP. J. Biol. Chem. 281, 11214-11224.
  25. Kikukawa, Y., Minami, R., Shimada, M., Kobayashi, M., Tanaka, K., Yokosawa, H., and Kawahara, H. (2005) Unique proteasome subunit Xrpn10c is a specific receptor for the antiapoptotic ubiquitin-like protein Scythe. FEBS J. 272, 6373|6386.
  26. Saeki, Y., Isono, E., Shimada, M., Kawahara, H., Yokosawa, H., and Toh-e, A. (2005) Knocking out ubiquitin proteasome system function in vivo and in vitro with genetically-encodable tandem ubiquitin. Methods Enzymol. 399, 64-74.
  27. Kinouchi, T., Ishiura, S., Mabuchi, Y., Urakami-Manaka, Y., Nishio, H., Nishiuchi, Y., Tsunemi, M., Takada, K., Watanabe, M., Ikeda, M., Matsui, H., Tomioka, S., Kawahara, H., Hamamoto, T., Suzuki, K., Kagawa, Y. (2004) Mammalian D-aspartyl endopeptidase: a scavenger for noxious racemized proteins in aging. Biochem. Biophys. Res. Comm. 314, 730-736.
  28. Tsukamoto, S., Yamashita, K., Tane, K., Kizu, R., Ohta, T., Matsunaga, S., Fusetani, N., Kawahara, H., and Yokosawa, H. (2004) Girolline, an antitumor compound isolated from a sponge, induces G2/M cell cycle arrest and accumulation of polyubiquitinated p53. Biol. Pharm. Bull. 27, 699-701.
  29. Saeki, Y., Isono, E., Oguchi, T., Shimada, M., Sone, T., Kawahara, H., Yokosawa, H., and Toh-e, A. (2004) Intracellularly inducible, ubiquitin hydrolase-insensitive tandem ubiquitins inhibit the 26S proteasome activity and cell division. Genes Genet. Syst. 79, 77-86.
  30. Sakata, E., Yamaguchi, Y., Kurimoto, E., Kikuchi, J., Yokoyama, S., Yamada, S., Kawahara, H., Yokosawa, H., Hattori, N., Mizuno, Y., Tanaka, K. and Kato. K. (2003) Parkin binds the Rpn10 subunit of the 26S proteasome with the ubiquitin-like domain. EMBO Rep. 4, 301-306.
  31. Sato, N., Kawahara, H., Toh-e, A. and Maeda, T. (2003) Phosphorelay-regulated degradation of the yeast Ssk1p response regulator by the ubiquitin-proteasome system. Mol. Cell. Biol. 23, 6662-6671.
  32. Kawai, N., Shimada, M., Kawahara, H., Satoh, N. and Yokosawa, H. (2003) Regulation of ascidian Rel by its alternative splice variant. Eur. J. Biochem. 270, 4459-4468.
  33. Shimada, M., Kawahara, H., and Doi, H. (2002) Novel family of CCCH type Zinc-finger proteins; MOE-1, -2 , and -3, participate in C. elegans oocyte maturation. Genes Cells 7, 933-947.
  34. Kikukawa, Y., Shimada, M., Suzuki, N., Tanaka, K., Yokosawa, H., and Kawahara, H. (2002) The 26S proteasome rpn10 gene encoding splicing isoforms: evolutional conservation of the genomic organization in vertebrates. Biol. Chem. 383, 1257-1261.
  35. Takahashi, N., Sasagawa, N., Usuki, F., Kino, Y., Kawahara, H., Sorimachi, H., Maeda, T., Suzuki, K., and Ishiura, S. (2001) Coexpression of the CUG-binding protein reduces DM protein kinase expression in COS cells. J. Biochem. 130, 581-587.
  36. Umeda, T., Kouchi, Z., Kawahara, H., Tomioka, S., Sasagawa, N.,Maeda, T., Sorimachi, H., Ishiura, S., and Suzuki, K. (2001) Limited proteolysis of filamin is catalyzed by caspase-3 in U937 and Jurkat cells. J. Biochem. 130, 535-542.
  37. Hata, S., Nishi, K., Kawamoto, T., Lee, H.J., Kawahara, H., Maeda, T., Sorimachi, H., Suzuki, K. (2001) Both the conserved and the unique gene structure of stomach-specific calpains reveal processes of calpain gene evolution. J. Mol. Evol. 53, 191-203.
  38. Kawahara, H., Philipova, R., Yokosawa, H., Patel, R., Tanaka, K. and Whitaker, M. (2000) Inhibiting proteasome activity causes over-replication of DNA and blocks entry into mitosis in sea urchin embryos. J. Cell Sci. 113, 2659-2670.
  39. Kawahara, H., Kasahara, M., Nishiyama, A., Ohsumi, K., Goto, T., Kishimoto, T., Saeki, Y., Yokosawa, H., Shimbara, N., Mutrata, S., Chiba, T., Suzuki, K. and Tanaka, K. (2000) Developmentally regulated alternative splicing of the Rpn10 gene generates multiple forms of 26S proteasomes. EMBO J. 19, 4144-4153.
  40. Murata, S., Kawahara, H., Tohma, S., Kasahara, K., Tanaka, K. and Chiba, T. (1999) Growth retardation of mice lacking the proteasome activator PA28 . J. Biol. Chem. 274, 38211-38215.
©2015 Department of Biological Sciences, Tokyo Metropolitan University