Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway
Project/Area Number |
26860224
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Multi-year Fund |
Research Field |
Pathological medical chemistry
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Research Institution | Niigata University |
Principal Investigator |
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Project Period (FY) |
2014-04-01 – 2016-03-31
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Project Status |
Completed (Fiscal Year 2015)
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Budget Amount *help |
¥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)
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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.
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Report
(3 results)
Research Products
(13 results)
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[Journal Article] Megalin-Mediated Tubuloglomerular Alterations in High-Fat Diet-Induced Kidney Disease2016
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
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Journal Title
J Am Soc Nephro
Volume: in press
Issue: 7
Pages: 1996-2008
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
Nat Commun.
Volume: 6
Issue: 1
Pages: 6116-6116
DOI
NAID
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[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.
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Journal Title
EMBO Rep.
Volume: 15
Issue: 5
Pages: 557-565
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway2014
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.
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Journal Title
J Biol Chem
Volume: 289
Issue: 36
Pages: 24944-24955
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Sqstm1-GFP knock-in mice reveal dynamic actions of Sqstm1 in living cells2016
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
Related Report
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[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
Related Report
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[Presentation] Proteasome dysfunction activates autophagy and the Keap1-Nrf2 system2014
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
Related Report