Phosphorylation of p62/Sqstm1 activates Nrf2 during selective autophagy

• Project/Area Number: 25460400
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Niigata University (2015); Tokyo Metropolitan Institute of Medical Science (2013-2014)
• Principal Investigator: ICHIMURA Yoshinobu 新潟大学, 医歯学系, 准教授 (80400993)
• Co-Investigator(Renkei-kenkyūsha): KOMATSU Masaaki 新潟大学, 医歯学系, 教授 (90356254)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 選択的オートファジー / p62/Sqstm1 / Keap1-Nrf2システム / リン酸化 / がん / p62 / Keap-Nrf2 / p62-Keap1-Nrf2 / リン酸化p62 / Keap1 / Nrf2

Outline of Final Research Achievements

In this study, we showed that Ser351 phosphorylation of p62 markedly increases p62’s binding affinity for Keap1, an adaptor of the Cul3 based E3 ubiquitin ligase complex for Nrf2 degradation. Therefore, p62 phosphorylation induces expression of cytoprotective Nrf2 target genes. Importantly, persistent phosphorylation of p62 was observed in hepatic adenoma in autophagy-deficient livers and in several cases of human hepatocellular carcinoma (HCC). Knockout of p62 gene in an HCC cell line markedly abrogated the growth, whereas forced expression of a phosphorylation mimic p62, but not a phosphorylation defective mutant, resulted in recovery of the growth defect. These results indicated the involvement of persistent activation of Nrf2 through the phosphorylation of p62 in hepatoma development.

Research Products

• [Journal Article] p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. (2015)
  • Author(s): Katsuragi Y, Ichimura Y, Komatsu M.
  • Journal Title: FEBS J. Volume: 282 Issue: 24 Pages: 4672-4678
  • DOI: 10.1111/febs.13540
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 選択的オートファジーと疾患 (2014)
  • Author(s): 一村義信
  • Journal Title: Thrombosis Medicine Volume: 4 Pages: 215-220
• [Journal Article] オートファジーとがん治療 (2014)
  • Author(s): 一村義信
  • Journal Title: 腫瘍内科 Volume: 13 Pages: 810-816
  • NAID: 40020137331
• [Journal Article] LC3B is indispensable for selective autophagy of p62 but not basal autophagy. (2014)
  • Author(s): Maruyama Y, Sou YS, Kageyama S, Takahashi T, Ueno T, Tanaka K, Komatsu M, Ichimura Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 446 Issue: 1 Pages: 309-315
  • DOI: 10.1016/j.bbrc.2014.02.093
  • Peer Reviewed
• [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] Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. (2013)
  • Author(s): Ichimura, Y., Waguri, S., Sou, Y., Kageyama, S., Hasegawa, J., Ishimura, R., Saito, T., Yang, Y., Kouno, T., Fukutomi, T., Hoshii, T., Atsushi, H., Takagi, K., Mizushima, T., Motohashi, H., Lee, M-S., Yoshimori, T., Tanaka, K., Yamamoto, M., and Komatsu, K.
  • Journal Title: Mol Cell Volume: 51 Issue: 5 Pages: 618-631
  • DOI: 10.1016/j.molcel.2013.08.003
  • Peer Reviewed / Open Access
• [Presentation] Screening of a Responsible Kinase(s) for p62/SQSTM1, an Autophagy-specific Substrate (2015)
  • Author(s): Yoshinobu Ichimura
  • Organizer: Symposium on Autophagy (A3)
  • Place of Presentation: Yonsei University, Seoul, Korea
  • Year and Date: 2015-10-29
  • Int'l Joint Research
• [Presentation] Phosphorylation of p62/Sqstm1 activates Nrf2 during selective autophagy (2015)
  • Author(s): Yoshinobu Ichimuura
  • Organizer: KEYSTONE SYMPOSIA on Molecular and Cellular Biology
  • Place of Presentation: Beaver Run Resort Breckenridge, Colorado, USA
  • Year and Date: 2015-06-20
  • Int'l Joint Research
• [Presentation] p62のリン酸化を介した選択的オートファジーとKeap1-Nrf2システムの連動 (2014)
  • Author(s): 一村義信、蔭山俊、和栗聡、水島恒裕、本橋ほづみ、山本雅之、小松雅明
  • Organizer: 新学術領域「オートファジーの集学的研究：分子基盤から疾患まで」第2回班会議・第8回オートファジー研究会
  • Place of Presentation: 「シャトレーゼ ガトーキングダム サッポロ」北海道札幌市
  • Year and Date: 2014-11-10 – 2014-11-11
• [Presentation] Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy (2013)
  • Author(s): 一村義信
  • Organizer: 第5回 医学研国際シンポジウム
  • Place of Presentation: 東京都医学総合研究所
  • Invited
• [Presentation] オートファジーとKeap1-Nrf2システムの接点：その異常と腫瘍増殖 (2013)
  • Author(s): 一村義信
  • Organizer: 第1回 がんと代謝研究会
  • Place of Presentation: 慶應義塾大学先端生命科学研究所
• [Presentation] オートファジーとKeap1-Nrf2システムの連動 (2013)
  • Author(s): 一村義信
  • Organizer: 新学術領域「オートファジーの集学的研究：分子基盤から疾患まで」第１回班会議
  • Place of Presentation: 静岡県掛川市 ヤマハリゾート「つま恋」
• [Remarks] 二つの主要な生体防御機構が連携するしくみを発見
  • URL: http://www.metro.tokyo.jp/INET/OSHIRASE/2013/09/20n96100.htm
• [Patent(Industrial Property Rights)] Reagent for diagnosing tumor, pharmaceutical composition, and screening method (2013)
  • Inventor(s): Komatsu M, Ichimura Y
  • Industrial Property Rights Holder: Komatsu M, Ichimura Y
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-06-05
  • Acquisition Date: 2015-07-28
  • Overseas