Quality control system for the newly synthesized tail-anchored proteins.

• Project/Area Number: 16K14699
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Functional biochemistry
• Research Institution: Tokyo Metropolitan University
• Principal Investigator: Kawahara Hiroyuki 首都大学東京, 理工学研究科, 教授 (70291151)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: BAG6 / ユビキチン / プロテアソーム / テイルアンカー蛋白質 / タンパク質品質管理 / タンパク質分解 / タンパク質凝集 / シグナル配列 / テイルアンカータンパク質 / BAG6複合体 / UBQLN4 / BUILDドメイン / 構造不良膜タンパク質 / TAタンパク質

Outline of Final Research Achievements

A portion of newly synthesized tail-anchored proteins tend to fail their correct assembly into the lumen of endoplasmic reticulum, thus resulting in the production of the defective species. Although the efficient degradation of these aggregation-prone polypeptides is crucial, the molecular mechanism of their elimination pathway has not been adequately characterized. In this study, we focused on one such cryptic portion of the defective transmembrane domain protein, and show that a part of these is produced as a labile species that is immediately targeted to the degradation pathway. We found that proteasomes are indispensable for elimination of mislocalized tail-anchored species. These observations suggest that protein degradation machinery acts as a critical factor for degradation of mislocalized tail-anchored proteins.

Research Products

• [Int'l Joint Research] University of California, San Francisco(U.S.A.)
• [Int'l Joint Research] University of Mancester(英国)
• [Int'l Joint Research] マンチェスター大学/生物学教室(英国)
• [Int'l Joint Research] フランクフルト大学/医学部(ドイツ)
• [Journal Article] ZFP36L2 is a cell cycle-regulated CCCH protein necessary for DNA lesion-induced S-phase arrest (2018)
  • Author(s): Noguchi Aya、Adachi Shungo、Yokota Naoto、Hatta Tomohisa、Natsume Tohru、Kawahara Hiroyuki
  • Journal Title: Biology Open Volume: 7
  • DOI: 10.1242/bio.031575
  • Peer Reviewed / Open Access
• [Journal Article] Deubiquitylases USP5 and USP13 are recruited to and regulate heat-induced stress granules through their deubiquitylating activities (2018)
  • Author(s): Xie Xuan、Matsumoto Shunsuke、Endo Akinori、Fukushima Toshiaki、Kawahara Hiroyuki、Saeki Yasushi、Komada Masayuki
  • Journal Title: Journal of Cell Science Volume: 131 Issue: 8 Pages: 210856-210856
  • DOI: 10.1242/jcs.210856
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel phosphorelay-dependent control of ZFP36L1 protein during the cell cycle. (2018)
  • Author(s): Kondo, M., Noguchi, A., Matsuura, Y., Shimada, M., Yokota, N., Kawahara, H.
  • Journal Title: Biochem. Biophys. Res. Comm. Volume: in press Issue: 2 Pages: 387-393
  • DOI: 10.1016/j.bbrc.2018.04.212
  • Peer Reviewed
• [Journal Article] Elimination of a signal-sequence uncleaved form of defective HLA protein through BAG6. (2017)
  • Author(s): Yamamoto, K., Hayashishita, M., Minami, S., Suzuki, K., Hagiwara, T., Noguchi, A., and Kawahara, H.
  • Journal Title: Sci. Rep. Volume: 7 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41598-017-14975-9
  • Peer Reviewed / Open Access
• [Journal Article] UBQLN4 recognizes mislocalized transmembrane domain proteins and targets these to proteasomal degradation. (2016)
  • Author(s): Rigel Suzuki and Hiroyuki Kawahara
  • Journal Title: EMBO Reports Volume: 未定 Issue: 6 Pages: 842-857
  • DOI: 10.15252/embr.201541402
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A conserved island of BAG6/Scythe is related to ubiquitin domains and participates in short hydrophobicity recognition. (2016)
  • Author(s): Tanaka, H., Takahashi, T., Xie, Y., Minami, R., Yanagi, Y., Hayashishita, M., Suzuki, R., Yokota, N., Shimada, M., Mizushima, T., Kuwabara, N., Kato, R., Kawahara, H.
  • Journal Title: FEBS J. Volume: 283 Issue: 4 Pages: 662-677
  • DOI: 10.1111/febs.13618
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The C-terminal cytoplasmic tail of hedgehog receptor Patched1 is a platform for E3 ubiquitin ligase complexes. (2016)
  • Author(s): Yamaki, Y., Kagawa, H., Hatta, T., Natsume, T., and Kawahara, H.
  • Journal Title: Mol. Cell. Biochem. Volume: 414 Issue: 1-2 Pages: 1-12
  • DOI: 10.1007/s11010-015-2643-4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 酸化ストレス存在下のBAG6複合体の役割 (2017)
  • Author(s): 横田直人、川原裕之
  • Organizer: 第４０回日本分子生物学会 第９０回日本生化学会 生命科学系合同年会
• [Presentation] ミスローカライズしたGPIアンカー型タンパク質の代謝におけるBAG6の機能解析 (2017)
  • Author(s): 大野靖枝、横田直人、川原 裕之
  • Organizer: 第４０回日本分子生物学会 第９０回日本生化学会 生命科学系合同年会
• [Presentation] BAG6依存的なRab-GTPase分解機構の解明 (2017)
  • Author(s): 高橋俊樹、川原 裕之
  • Organizer: 第４０回日本分子生物学会 第９０回日本生化学会 生命科学系合同年会
• [Presentation] ミトコンドリアタンパク質を標的とするBAG6新規機能の探索 (2017)
  • Author(s): 林下瑞希、川原 裕之
  • Organizer: 第４０回日本分子生物学会 第９０回日本生化学会 生命科学系合同年会
• [Presentation] UBQLN4の基質認識機構の解明 (2017)
  • Author(s): 鈴木勘司、鈴木理滋、川原裕之
  • Organizer: 第４０回日本分子生物学会 第９０回日本生化学会 生命科学系合同年会
• [Presentation] ミトコンドリアを標的としたBAG6新規機能の探索 (2016)
  • Author(s): 林下瑞希
  • Organizer: 第39回日本分子生物学会大会
  • Place of Presentation: パシフィコ横浜，横浜市
  • Year and Date: 2016-11-30
• [Presentation] ミスローカライズしたHLAの代謝におけるBAG6の機能 (2016)
  • Author(s): 山本昂季
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター，仙台市
  • Year and Date: 2016-09-27
• [Presentation] ＵＢＱＬＮ４による膜タンパク質品質管理機構の解明 (2016)
  • Author(s): 鈴木理滋
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター，仙台市
  • Year and Date: 2016-09-27
• [Presentation] BAG6-Ubl4a複合体による不良膜タンパク質の品質管理機構 (2016)
  • Author(s): 戸島麻子
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター，仙台市
  • Year and Date: 2016-09-26
• [Presentation] BAG6による不良タンパク質認識機構の解明 (2016)
  • Author(s): 高橋俊樹
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター，仙台市
  • Year and Date: 2016-09-26
• [Remarks] 首都大学東京 細胞生化学研究室ホームページ
  • URL: http://www.biol.se.tmu.ac.jp/labo.asp?ID=celche
• [Remarks] 首都大学東京理工学研究科生命科学専攻細胞生化学研究室ホームページ１
  • URL: http://www.biol.se.tmu.ac.jp/labo.asp?ID=celche
• [Remarks] 首都大学東京理工学研究科生命科学専攻細胞生化学研究室ホームページ２
  • URL: http://www.comp.tmu.ac.jp/saisei/index.html