Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway

• Project/Area Number: 26860224
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Niigata University
• Principal Investigator: KAGEYAMA Shun 新潟大学, 医歯学系, 助教 (30624225)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: オートファジー / プロテアソーム / ユビキチン / 凝集体 / Sqstm1/p62 / Nrf2 / Keap1 / ユビキチン-プロテアソームシステム / Atg7 / psmc1 / Sqstm1-GFP / p62

Outline of Final Research Achievements

The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. These pathways are interdependent, and dysfunction in either pathway causes accumulation of ubiquitin-positive aggregates. To evaluate in vivo compensatory action against proteasomal dysfunction, we developed mice with reduced proteasome activity in their livers. The mutant mice exhibited severe liver damage, accompanied by formation of aggregates positive for ubiquitin and p62, an adaptor protein for both selective autophagy and the anti-oxidative Keap1-Nrf2 pathway. These aggregates were selectively entrapped by autophagosomes, and pathological features of mutant livers were exacerbated by simultaneous suppression of autophagy. Furthermore, defective proteasome function led to transcriptional activation of the Nrf2, which served as a physiological adaptation. Our in vivo data suggest that cells contain networks of cellular defense mechanisms against defective proteostasis.

Research Products

• [Journal Article] Megalin-Mediated Tubuloglomerular Alterations in High-Fat Diet-Induced Kidney Disease (2016)
  • Author(s): Kuwahara S, Hosojima M, Kaneko R, Aoki H, Nakano D, Sasagawa T, Kabasawa H, Kaseda R, Yasukawa R, Ishikawa T, Suzuki A, Sato H, Kageyama S, Tanaka T, Kitamura N, Narita I, Komatsu M, Nishiyama A, Saito A
  • Journal Title: J Am Soc Nephro Volume: in press Issue: 7 Pages: 1996-2008
  • DOI: 10.1681/asn.2015020190
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sqstm1-GFP knock-in mice reveal dynamic actions of Sqstm1 during autophagy and under stress conditions in living cells. (2015)
  • Author(s): Atsushi Eino, Shun Kageyama, Takefumi Uemura, Hiromichi Annoh, Tetsuya Saito, Ichiei Narita, Satoshi Waguri, Masaaki Komatsu.
  • Journal Title: Journal of Cell Science Volume: 128 Pages: 4453-4461
  • DOI: 10.1242/jcs.180174
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The unexpected role of polyubiquitin chains in the formation of fibrillar aggregates. (2015)
  • Author(s): Morimoto D,Walinda E, Fukada H, Sou YS, Kageyama S, Hoshino M, Fujii T, Tsuchiya H, Saeki Y, Arita K, Ariyoshi M, Tochio H, Iwai K, Namba K, Komatsu M, Tanaka K, Shirakawa M.
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 6116-6116
  • DOI: 10.1038/ncomms7116
  • NAID: 120005528125
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] オートファジーの誘導 (2015)
  • Author(s): 蔭山俊
  • Journal Title: THE LUNG perspectives Volume: 23 Pages: 47-51
• [Journal Article] Structural determinants in GABARAP required for the selective binding and recruitment of ALFY to LC3B-positive structures. (2014)
  • Author(s): Lystad, AH., Ichimura, Y., Takagi, K., Yang, Y., Pankiv, S., Kanegae, Y., Kageyama, S., Suzuki, M., Saito, I., Mizushima,T., *Komatsu, M., *Simonsen, A.
  • Journal Title: EMBO Rep. Volume: 15 Issue: 5 Pages: 557-565
  • DOI: 10.1002/embr.201338003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway (2014)
  • Author(s): Kageyama S, Sou YS, Uemura T, Kametaka S, Saito T, Ishimura R, Kouno T, Bedford L, Mayer RJ, Lee MS, Yamamoto M, Waguri S, Tanaka K, and Komatsu M.
  • Journal Title: J Biol Chem Volume: 289 Issue: 36 Pages: 24944-24955
  • DOI: 10.1074/jbc.m114.580357
  • Peer Reviewed / Open Access
• [Journal Article] オートファジーと疾患-Autophagy and disease states- (2014)
  • Author(s): 小松雅明、蔭山俊
  • Journal Title: 新潟県医師会報 Volume: 774 Pages: 1-9
• [Presentation] Sqstm1-GFP knock-in mice reveal dynamic actions of Sqstm1 in living cells (2016)
  • Author(s): Shun Kageyama, Atsushi Eino, Takefumi Uemura, Satoshi Waguri and Masaaki Komatsu
  • Organizer: Joint Japan-Korea Young Investigator Conference on Autophagy (A3)
  • Place of Presentation: NIIGATA MEDICAL PROFESSIONALS DEVELOPMENT CENTER, NIIGATA UNIVERSITY, 757, Ichibancho, Asahimachidori, Chuo-ku, Niigata-shi, Niigata, JAPAN
  • Year and Date: 2016-02-18
• [Presentation] Alfyによるメンブレントラフィック制御 (2015)
  • Author(s): 蔭山 俊、和栗 聡、鐘ヶ江 裕美、曽 友深、一村 義信、斎藤 泉、福田 光則、小松 雅明
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会）
  • Place of Presentation: 神戸国際展示場 1号館1F、兵庫県神戸市中央区港島中町６丁目１１－１
  • Year and Date: 2015-12-02
• [Presentation] Sqstm1-GFPノックインマウスを用いたSqstm1/p62の動態解析 (2015)
  • Author(s): Eino A, Kageyama S, Uemura T, Annoh H, Saito T, Narita I, Waguri S, Komatsu M
  • Organizer: 第3 回新学術「オートファジー」班会議 (第9 回オートファジー研究会
  • Place of Presentation: 淡路夢舞台国際会議場、兵庫県淡路市夢舞台１
  • Year and Date: 2015-11-16
• [Presentation] Proteasome Dysfunction Activates Autophagy and the Keap1-Nrf2 Pathway (2015)
  • Author(s): S Kageyama; Y Sou; T Uemura; S Kametaka; T Saito; R Ishimura; T Kouno; R Mayer; L Bedford; M Lee; M Yamamoto; S Waguri; K Tanaka; M Komatsu
  • Organizer: 2015 Keystone Symposia Conference E6: Autophagy
  • Place of Presentation: Beaver Run Resort, Breckenridge, Colorado
  • Year and Date: 2015-06-21
• [Presentation] プロテアソーム障害は選択的オートファジーとKeap1-Nrf2システムを活性化する (2014)
  • Author(s): 蔭山俊、曽友深、植村武文、亀高諭、斉藤哲也、石村亮輔、河野亜華、Lynn Bedford、R. John Mayer、Myung-Shik Lee、山本 雅之、和栗聡、田中啓二、小松雅明
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜 展示ホール
  • Year and Date: 2014-11-26
• [Presentation] Proteasome dysfunction activates autophagy and the Keap1-Nrf2 system (2014)
  • Author(s): Shun Kageyama, Yu-shin Sou, Takefumi Uemura, Satoshi Kametaka, Tetsuya Saito, Ryosuke Ishimura, Tsuguka Kouno, Lynn Bedford, R. John Maye, Myung-Shik Lee, Masayuki Yamamoto, Satoshi Waguri, Keiji Tanaka, and Masaaki Komatsu
  • Organizer: 第8回オートファジー研究会・第2回新学術「オートファジー」班会議
  • Place of Presentation: シャトレーゼ ガトーキングダム サッポロ
  • Year and Date: 2014-11-10