Elucidation of the role of linear polyubiquitin chains in TNF-induced cell death

• Project/Area Number: 24790215
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General physiology
• Research Institution: Kyoto University
• Principal Investigator: NAKAHARA Masaki 京都大学, 医学(系)研究科(研究院), 助教 (60542967)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: ユビキチン / 細胞死 / NF-kappaB / TNF-alpha / アポトーシス / NF-kappaN / 直鎖状ポリユビキチン鎖 / NF-κB / TNF

Research Abstract

SHARPIN and HOIL-1L function as accessory subunits of a linear ubiquitin chain assembly complex (LUBAC), which plays an important role in NF-kappaB activation. However, there still remains to elucidate the functional difference between SHARPIN and HOIL-1L. Here we showed that SHARPIN deficiency sensitized mice and mouse embryonic fibroblasts (MEFs) to tumor necrosis factor TNF-alpha-induced apoptosis more severely than HOIL-1L deficiency. In contrast, NF-kappaB activation by TNF-alpha was slightly more impaired in Hoil-1 deficient MEFs than in Sharpincpdm MEFs. Overexpression of HOIL-1L restored NF-kappaB activation in Sharpincpdm MEFs, but did not block TNF-alpha-induced apoptosis completely. These results suggest that SHARPIN, but not HOIL-1L, inhibits TNF-alpha-induced apoptosis in an NF-kappaB-independent manner.

Research Products

• [Journal Article] Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells (2013)
  • Author(s): Sasaki Y, Sano S, Nakahara M, Murata S, Kometani K, Aiba Y, Sakamoto S, Watanabe Y, Tanaka K, Kurosaki T, Iwai K
  • Journal Title: EMBO J Volume: 32 Pages: 2463-2463
  • Peer Reviewed
• [Journal Article] Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells. (2013)
  • Author(s): Sasaki Y, Sano S, Nakahara M, Murata S, Kometani K, Aiba Y, Sakamoto S, Watanabe Y, Tanaka K, Kurosaki T, Iwai K
  • Journal Title: EMBO J Volume: 32 Pages: 2463-2463
  • Peer Reviewed
• [Presentation] 直鎖状ポリユビキチン鎖生成リガーゼ構成分子であるSHARPINおよびHOIL-1LのTNF誘導細胞死における機能的役割の違い (2013)
  • Author(s): 中原匡咲
  • Organizer: 科学研究費補助金新学術領域研究「ユビキチンネオバイオロジー」第1回班会議
  • Place of Presentation: 千里ライフサイエンスセンター
• [Presentation] 直鎖状ポリユビキチン鎖生成リガーゼ構成分子である SHARPINおよびHOIL-1LのTNF誘導細胞死における機能的役割の違い (2013)
  • Author(s): 中原 匡咲
  • Organizer: 科学研究費補助金新学術領域研究 「ユビキチンネオバイオロジー」 第1回班会議
  • Place of Presentation: 千里ライフサイエンスセンター
• [Presentation] NF-κB活性化および細胞死におけるSHARPINとHOIL-1Lの機能的役割の解明 (2012)
  • Author(s): 中原匡咲
  • Organizer: 第4回シグナルネットワーク研究会
  • Place of Presentation: 兵庫県淡路島淡路夢舞台
  • Year and Date: 2012-05-18
• [Presentation] SHARPIN欠損変異マウスにおけるTNF依存的な細胞死の亢進メカニズム (2012)
  • Author(s): 中原匡咲
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場・マリンメッセ
• [Presentation] SHARPIN 欠損変異マウスにおけるTNF 依存的な細胞死の亢進メカニズム (2012)
  • Author(s): 中原 匡咲
  • Organizer: 第35回（2012年）日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場・マリンメッセ
• [Presentation] NF-κB活性化および細胞死におけるSHARPINとHOIL-1Lの機能的役割の解明
  • Author(s): 中原 匡咲
  • Organizer: 第4回 シグナルネットワーク研究会
  • Place of Presentation: 兵庫県淡路島 淡路夢舞台