Novel regulatory mechanism of TFEB by autophagy genes during lysosomal damage response

• Project/Area Number: 17H05064
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Osaka University
• Principal Investigator: Nakamura Shuhei 大阪大学, 高等共創研究院, 准教授 (00510611)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥24,180,000 (Direct Cost: ¥18,600,000、Indirect Cost: ¥5,580,000); Fiscal Year 2019: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000); Fiscal Year 2018: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000); Fiscal Year 2017: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: リソソーム / TFEB / オートファジー / 転写因子 / 腎臓 / 生活習慣病

Outline of Final Research Achievements

Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here, we found that during the lysosomal damage response, Transcription factor EB (TFEB), a master transcriptional regulator of lysosomal biogenesis and autophagy, was activated dependent upon the non-canonical LC3 function. Furthermore, we demonstrated the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results revealed novel and unexpected mechanisms of TFEB activation by LC3 and their physiological relevance during the lysosomal damage response.

Academic Significance and Societal Importance of the Research Achievements

転写因子TFEBは飢餓などの様々なストレスで活性化され、オートファジーおよびリソソーム生合成を転写レベルで制御するマスターレギュレーターである。近年TFEBの活性化は神経変性疾患、脂質代謝の改善、健康寿命延長につながり有益となることが示された為、その制御機構に注目が集まっている。本研究により同定したTFEBの新規制御機構は我々が明らかにしたシュウ酸カルシウム腎症のみならず神経変性疾患などリソソーム損傷を伴うことが知られているその他の疾患においても働いている可能性があり、今後のさらなる解析によりこの機構をもとにした治療法確立に寄与できる可能性がある。

Research Products

• [Int'l Joint Research] TIGEM(イタリア)
• [Int'l Joint Research] Andrea Ballabio/TIGEM(イタリア)
• [Journal Article] Starvation causes female-to-male sex reversal through lipid metabolism in the teleost fish, medaka (Olyzias latipes) (2020)
  • Author(s): Sakae Yuta、Oikawa Akira、Sugiura Yuki、Mita Masatoshi、Nakamura Shuhei、Nishimura Toshiya、Suematsu Makoto、Tanaka Minoru
  • Journal Title: Biology Open Volume: 9 Issue: 4 Pages: 1-12
  • DOI: 10.1242/bio.050054
  • Peer Reviewed / Open Access
• [Journal Article] 【オートファジー-分子機構・生物学的意義・疾患との関わり】オートファジーと疾患 オートファジーと寿命延長 (2020)
  • Author(s): 中村修平、吉森保
  • Journal Title: 医学のあゆみ Volume: 272 Pages: 926-932
• [Journal Article] 長寿フロントライン 加齢によるオートファジー低下機構の解明 (2020)
  • Author(s): 中村修平
  • Journal Title: Aging & Health Volume: 28 Pages: 38-41
  • NAID: 40022148542
• [Journal Article] Suppression of autophagic activity by Rubicon is a signature of aging. (2019)
  • Author(s): Nakamura S, Oba M, Suzuki M, Takahashi A, Yamamuro T, Fujiwara M, Ikenaka K, Minami S, Tabata N, Yamamoto K, Kubo S, Tokumura A, Akamatsu K, Miyazaki Y, Kawabata T, Hamasaki M, Fukui K, Sango K, Watanabe Y, Takabatake Y, Kitajima T, Okada Y, Mochizuki H, Isaka Y, Antebi A, Yoshimori T.
  • Journal Title: Nat Commun Volume: 10 Issue: 1 Pages: 847-847
  • DOI: 10.1038/s41467-019-08729-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics (2018)
  • Author(s): Chang C, Young LN, Morris KL, von Buelow S, Schoeneberg J, Yamamoto-Imoto H, Oe Y, Yamamoto K, Nakamura S, Stjepanovic G, Hummer G, Yoshimori T, Hurley JH
  • Journal Title: Mol. Cell. Volume: 73 Issue: 2 Pages: 339-353
  • DOI: 10.1016/j.molcel.2018.10.035
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Autophagy and Longevity (2018)
  • Author(s): Nakamura, S. and *Yoshimori, T
  • Journal Title: Mol. Cells Volume: 41 Pages: 65-72
  • NAID: 40022577476
  • Peer Reviewed / Open Access
• [Journal Article] New insights into autophagosome-lysosome fusion. (2017)
  • Author(s): Nakamura S, Yoshimori T.
  • Journal Title: J Cell Science. 130. 2017. p1209-1216 Volume: 130 Issue: 7 Pages: 1209-1216
  • DOI: 10.1242/jcs.196352
  • Peer Reviewed
• [Journal Article] Essential role for GABARAP autophagy proteins in interferon-inducible GTPase-mediated host defense (2017)
  • Author(s): Sasai Miwa、Sakaguchi Naoya、Ma Ji Su、Nakamura Shuhei、Kawabata Tsuyoshi、Bando Hironori、Lee Youngae、Saitoh Tatsuya、Akira Shizuo、Iwasaki Akiko、Standley Daron M、Yoshimori Tamotsu、Yamamoto Masahiro
  • Journal Title: Nature Immunology Volume: 18 Issue: 8 Pages: 899-910
  • DOI: 10.1038/ni.3767
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Small nucleoli are a cellular hallmark of longevity. (2017)
  • Author(s): iku, V., Jain, C, Raz, Y., Nakamura, S., Heestand, B., Liu, W., Spath, M., Suchiman, H., Muller, R., Slagboom, E., Partridge, L. and *Antebi, A.
  • Journal Title: Nat. Commun. Volume: 8 Issue: 1 Pages: 16308-16308
  • DOI: 10.1038/ncomms16083
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 哺乳類オートファジーの分子機構と癌における役割 (2017)
  • Author(s): 中村 修平、吉森 保
  • Journal Title: The Word on Digestive Surgery Volume: 18 Pages: 2-3
• [Book] オートファジー 分子メカニズムの理解から病態の解明まで (2017)
  • Author(s): 中村 修平、吉森 保(第20章 「オートファジーと老化」分担執筆)
  • Total Pages: 241
  • Publisher: 南山堂
  • ISBN: 9784525134815
• [Book] The オートファジー 研究者たちの集大成が見える最新ビジュアルテキスト (2017)
  • Author(s): 中村 修平、吉森 保 (「オートファゴソーム成熟と融合の分子機構」分担執筆)
  • Total Pages: 224
  • Publisher: 羊土社
  • ISBN: 9784758103657