Analysis of Ulk1 phosphorylation to control alternative autophagy and elucidation of its physiological and pathological significance

• Project/Area Number: 18K06210
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Torii Satoru 東京医科歯科大学, 難治疾患研究所, プロジェクト准教授 (10444001)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: オートファジー / Ulk1 / リン酸化 / RIPK3 / Atg5 / キナーゼ

Outline of Final Research Achievements

Autophagy is a catabolic process in which cellular contents, such as proteins, are degraded. In addition to canonical autophagy, my colleagues previously discovered alternative autophagy. Ulk1 is involved in both autophagic pathways. However, the detailed molecular mechanisms of Ulk1 regulation remains unclear. In this study, we find that Ulk1 is phosphorylated at Ser746 in the initiation of alternative autophagy, but not that of canonical autophagy. The activation of alternative autophagy in tissues can be observed by using anti-p-Ulk1746 antibody.

Academic Significance and Societal Importance of the Research Achievements

オートファジーは様々な生体現象や疾患にとって重要であることがわかっているが、その中で二種類のオートファジーが、どのように使い分けられているのかは、これまで不明だった。本研究は、その制御メカニズムを発見したもので、オートファジー研究に重要な知見を与えるものである。さらに、今回作製したUlk1の746番目セリンのリン酸化抗体を用いることにより、新規オートファジーを捕捉することが初めて可能となったことから、新規オートファジーに関する研究の今後の発展が期待でき、将来的にはオートファジー異常に関連した疾患治療のための医薬設計に指針を与える可能性がある。

Research Products

• [Journal Article] Homeostatic p62 levels and inclusion body formation in CHCHD2 knockout mice (2021)
  • Author(s): Sato Shigeto、Noda Sachiko、Torii Satoru、Amo Taku、Ikeda Aya、Funayama Manabu、Yamaguchi Junji、Fukuda Takahiro、Kondo Hiromi、Tada Norihiro、Arakawa Satoko、Watanabe Masahiko、Uchiyama Yasuo、Shimizu Shigeomi、Hattori Nobutaka
  • Journal Title: Human Molecular Genetics Volume: 30 Issue: 6 Pages: 443-453
  • DOI: 10.1093/hmg/ddab057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1 (2021)
  • Author(s): Daniel J Klionsky、Shu Aizawa、Amal Kamal Abdel-Aziz、Sara Abdelfatah、Mahmoud Abdellatif、Asghar Abdoli、Steffen Abel、Hagai Abeliovich、Marie H Abildgaard、Yakubu Princely Abudu、Abraham Acevedo-Arozena、Iannis E Adamopoulos、Khosrow Adeli、Timon E Adolph、Annagrazia Adornetto、Elma Aflaki、Galila Agam et al.
  • Journal Title: Autophagy Volume: 17 Issue: 1 Pages: 1-382
  • DOI: 10.1080/15548627.2020.1797280
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Wipi3 is essential for alternative autophagy and its loss causes neurodegeneration (2020)
  • Author(s): Yamaguchi Hirofumi、Honda Shinya、Torii Satoru、Shimizu Kimiko、Katoh Kaoru、Miyake Koichi、Miyake Noriko、Fujikake Nobuhiro、Sakurai Hajime Tajima、Arakawa Satoko、Shimizu Shigeomi
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 5311-5311
  • DOI: 10.1038/s41467-020-18892-w
  • Peer Reviewed / Open Access
• [Journal Article] Autophagy involvement in oncogenesis (2020)
  • Author(s): Torii Satoru、Honda Shinya、Murohashi Michiko、Yamaguchi Hirofumi、Shimizu Shigeomi
  • Journal Title: Cancer Science Volume: 111 Issue: 11 Pages: 3993-3999
  • DOI: 10.1111/cas.14646
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of phosphorylation of ULK1 in alternative autophagy (2020)
  • Author(s): Torii Satoru、Shimizu Shigeomi
  • Journal Title: Autophagy Volume: 16 Issue: 8 Pages: 1532-1533
  • DOI: 10.1080/15548627.2020.1776476
  • Peer Reviewed
• [Journal Article] Identification of a phosphorylation site on Ulk1 required for genotoxic stress-induced alternative autophagy (2020)
  • Author(s): Torii Satoru、Yamaguchi Hirofumi、Nakanishi Akira、Arakawa Satoko、Honda Shinya、Moriwaki Kenta、Nakano Hiroyasu、Shimizu Shigeomi
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 1754-1754
  • DOI: 10.1038/s41467-020-15577-2
  • Peer Reviewed / Open Access
• [Journal Article] ER-resident sensor PERK is essential for mitochondrial thermogenesis in brown adipose tissue. (2020)
  • Author(s): Kato H, Okabe K, Miyake M, Hattori K, Fukaya T, Tanimoto K, Beini S, Mizuguchi M, Torii S, Arakawa S, Ono M, Saito Y, Sugiyama T, Funatsu T, Sato K, Shimizu S, Oyadomari S, Ichijo H, Kadowaki H, Nishitoh H.
  • Journal Title: Life science alliance Volume: 3 Issue: 3 Pages: 201900576-201900576
  • DOI: 10.26508/lsa.201900576
  • NAID: 120006980545
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial E3 Ubiquitin Ligase Parkin: Relationships with Other Causal Proteins in Familial Parkinson's Disease and Its Substrate-Involved Mouse Experimental Models. (2020)
  • Author(s): Torii S, Kasai S, Yoshida T, Yasumoto KI, Shimizu S.
  • Journal Title: International journal of molecular sciences Volume: 21 Issue: 4 Pages: 1202-1202
  • DOI: 10.3390/ijms21041202
  • Peer Reviewed / Open Access
• [Journal Article] Receptor-Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells. (2020)
  • Author(s): Otsubo K, Maeyashiki C, Nibe Y, Tamura A, Aonuma E, Matsuda H, Kobayashi M, Onizawa M, Nemoto Y, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Torii S, Itakura E, Watanabe M, Oshima S.
  • Journal Title: FEBS letters Volume: 594 Issue: 10 Pages: 1586-1595
  • DOI: 10.1002/1873-3468.13748
  • Peer Reviewed / Open Access
• [Journal Article] Association Between Atg5-independent Alternative Autophagy and Neurodegenerative Diseases. (2020)
  • Author(s): Honda S, Arakawa S, Yamaguchi H, Torii S, Tajima Sakurai H, Tsujioka M, Murohashi M, Shimizu S.
  • Journal Title: Journal of molecular biology Volume: 432 Issue: 8 Pages: 2622-2632
  • DOI: 10.1016/j.jmb.2020.01.016
  • Peer Reviewed / Open Access
• [Journal Article] Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming (2019)
  • Author(s): Muraoka Naoto、Nara Kaori、Tamura Fumiya、Kojima Hidenori、Yamakawa Hiroyuki、Sadahiro Taketaro、Miyamoto Kazutaka、Isomi Mari、Haginiwa Sho、Tani Hidenori、Kurotsu Shota、Osakabe Rina、Torii Satoru、Shimizu Shigeomi、Okano Hideyuki、Sugimoto Yukihiko、Fukuda Keiichi、Ieda Masaki
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 674-674
  • DOI: 10.1038/s41467-019-08626-y
  • NAID: 120007128245
  • Peer Reviewed / Open Access
• [Presentation] 新規オートファジーに必須なUlk1のリン酸化とネクロプトーシス実行因子RIPK3の関与. (2020)
  • Author(s): 鳥居暁, 山口啓史, 中西啓, 荒川聡子, 本田真也, 森脇健太, 中野裕康, 清水重臣.
  • Organizer: 第１回細胞死コロキュアム
  • Invited
• [Presentation] Regulation of phosphorylation of Ulk1 in alternative autophagy. (2020)
  • Author(s): Torii S, Yamaguchi H, Nakanishi A, Arakawa S, Honda S, Moriwaki K, Nakano H, and Shimizu S.
  • Organizer: The 15th International Symposium of the Institute Network for Biomedical Sciences.
  • Int'l Joint Research / Invited
• [Presentation] RIPK3によるDNA傷害依存的な新規オートファジーの制御. (2020)
  • Author(s): 鳥居暁, 山口啓史, 中西啓, 荒川聡子, 本田真也, 森脇健太, 中野裕康, 清水重臣.
  • Organizer: 第93回日本生化学会大会
  • Invited
• [Presentation] The role of PPM1D in regulating DNA damage-induced autophagy. (2018)
  • Author(s): Torii S, Yoshida T, Arakawa S, Honda S and Shimizu S.
  • Organizer: Workshop on Frontiers in Phosphatase Research and Drug Discovery (ICPP13)
  • Int'l Joint Research
• [Presentation] オートファジーによるDNA傷害誘導性アポトーシスの制御 (2018)
  • Author(s): 鳥居暁, 吉田達士, 荒川聡子, 本田真也, 清水重臣.
  • Organizer: 第27回日本Cell death学会学術集会
  • Invited
• [Presentation] Regulation of DNA damage-induced apoptosis by autophagy. (2018)
  • Author(s): Torii S, Yoshida T, Arakawa S, Honda S and Shimizu S.
  • Organizer: Australia-Japan Meeting on Cell Death.
  • Int'l Joint Research
• [Remarks] 「二種類のオートファジーを使い分けるメカニズムの解明」
  • URL: https://www.tmd.ac.jp/archive-tmdu/kouhou/20200410_1.pdf
• [Remarks] TMDU Research Activities 2020-2021
  • URL: https://www.youtube.com/watch?v=MhipOLe-COU&feature=youtu.be