The molecular mechanism regulating ubiquitination of aberrant plasma membrane protein

• Project/Area Number: 25893275
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: Kwansei Gakuin University
• Principal Investigator: OKIYONEDA Tsukasa 関西学院大学, 理工学部, 准教授 (90398248)
• Project Period (FY): 2013-08-30 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 脱ユビキチン化 / CFTR / タンパク質品質管理 / ユビキチン

Outline of Final Research Achievements

Here, we sought to identify the deubiquitination enzyme (DUB) involved in the peripheral protein quality control mechanism that eliminates aberrant plasma membrane proteins such as ΔF508 CFTR. Analysis of a panel of DUB inhibitors discovered that inhibition of proteasome-associated DUB increased the cell surface expression and stability of ΔF508 CFTR. Moreover, endocytosis of ΔF508 CFTR was dramatically inhibited by inhibitors of proteasome-associated DUB. These results provide a novel regulatory mechanism that the proteasome-associated deubiquitination stimulates the elimination of aberrant plasma membrane proteins from the cell surface.

Research Products

• [Journal Article] Peripheral quality control mechanism eliminating aberrant proteins from the plasma membrane (2014)
  • Author(s): Okiyoneda T
  • Journal Title: Seikagaku Volume: Feb;86(1) Pages: 54-8
  • NAID: 40020011065
  • Peer Reviewed
• [Journal Article] Mechanism-based corrector combination restores ΔF508-CFTR folding and function. (2013)
  • Author(s): Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H, Roldan A, Verkman AS, Kurth M, Simon A, Hegedus T, Beekman JM, Lukacs GL
  • Journal Title: Nat Chem Biol Volume: Jul;9(7) Issue: 7 Pages: 444-54
  • DOI: 10.1038/nchembio.1253
  • Peer Reviewed
• [Journal Article] Ubiquitination-dependent quality control of hERG K+ channel with acquired and inherited conformational defect at the plasma membrane. (2013)
  • Author(s): Apaja PM, Foo B, Okiyoneda T, Valinsky WC, Barriere H, Atanasiu R, Ficker E, Lukacs GL, Shrier A.
  • Journal Title: Mol Biol Cell Volume: Dec;24(24) Issue: 24 Pages: 3787-804
  • DOI: 10.1091/mbc.e13-07-0417
  • Peer Reviewed
• [Presentation] ユビキチン化による膜タンパク質CFTRの品質管理機構 (2014)
  • Author(s): 沖米田 司
  • Organizer: 日本生化学会大会
  • Place of Presentation: 国立京都国際会館（京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] CFTR quality control checkpoints as drug target (2014)
  • Author(s): Tsukasa Okiyoneda
  • Organizer: Cystic Fibrosis in Asia from baslcs to clinics
  • Place of Presentation: 名古屋大学（名古屋市）
  • Year and Date: 2014-09-29 – 2014-09-30
  • Invited
• [Presentation] Post-ERにおける膜タンパク質CFTR のプロテオスタシス
  • Author(s): 沖米田 司
  • Organizer: 第３６回日本分子生物学会年会
  • Place of Presentation: 神戸ポートピアホテル（神戸）
  • Invited
• [Presentation] 嚢胞性線維症の薬物療法を目指した CFTR コレクターの分類と相乗効果
  • Author(s): 沖米田 司
  • Organizer: 日本薬学会第１３４回年会
  • Place of Presentation: 熊本大学（熊本）
  • Invited
• [Remarks] 沖米田研究室 web ページ
  • URL: http://sci-tech.ksc.kwansei.ac.jp/~okiyoneda/okilab.html
• [Remarks] 関西学院大学 理工学部 沖米田研究室
  • URL: http://sci-tech.ksc.kwansei.ac.jp/~okiyoneda/okilab.html