Analyses of a novel type of autophagy

• Project/Area Number: 24680038
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Neuroscience in general
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: Kabuta Tomohiro 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第四部, 室長 (70535765)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥26,780,000 (Direct Cost: ¥20,600,000、Indirect Cost: ¥6,180,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2014: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2013: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2012: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: リソソーム / オートファジー / RNA分解 / 選択的オートファジー / RNautophagy / DNautophagy / SIDT2 / DNA分解 / LAMP2 / LAMP2C / C9ORF72 / リピートRNA / 細胞内分解 / 膜蛋白質 / 選択的分解 / RNA / RNオートファジー

Outline of Final Research Achievements

A proper intracellular degradation of biological macromolecules is essential for the maintenance of biological homeostasis. Dysfunction of the degradation systems is thought to be involved in various diseases, such as neurodegenerative disorders. Therefore, it is important to clarify intracellular degradation systems. In this study, we discovered a novel degradation system, RNautophagy and DNautophagy, where RNA and DNA are directly taken up by lysosomes in an ATP-dependent manner and degraded, respectively. We also found that one of the physiological functions of RNautophagy is a constitutive degradation of intracellular RNA.

Research Products

• [Journal Article] Lysosomal putative RNA transporter SIDT2 mediates direct uptake of RNA by lysosomes (2016)
  • Author(s): Shu Aizawa, Yuuki Fujiwara, Viorica Raluca Contu, Katsunori Hase, Masayuki Takahashi, Hisae Kikuchi, Chihana Kabuta, Keiji Wada & Tomohiro Kabuta
  • Journal Title: Autophagy Volume: 12 Issue: 3 Pages: 565-78
  • DOI: 10.1080/15548627.2016.1145325
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] RNautophagy/DNautophagy possesses selectivity for RNA/DNA substrates. (2015)
  • Author(s): Hase K, Fujiwara Y, Kikuchi H, Aizawa S, Hakuno F, Takahashi S, Wada K, Kabuta T.
  • Journal Title: Nucleic Acids Res Volume: 43 Issue: 13 Pages: 6439-6449
  • DOI: 10.1093/nar/gkv579
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An RNautophagy/DNautophagy receptor, LAMP2C, possesses an arginine-rich motif that mediates RNA/DNA-binding (2015)
  • Author(s): Fujiwara Y, Hase K, Wada K, Kabuta T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 460 Issue: 2 Pages: 281-286
  • DOI: 10.1016/j.bbrc.2015.03.025
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lysosomal-associated membrane protein 2 Isoforms Are Differentially Affected in Early Parkinson's Disease. (2015)
  • Author(s): Murphy KE, Gysbers AM, Abbott SK, Spiro AS, Furuta A, Cooper A, Garner B, Kabuta T, Halliday GM
  • Journal Title: Mov Disord Volume: in press Issue: 12 Pages: 1639-1647
  • DOI: 10.1002/mds.26141
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Property of lysosomal storage disease associated with midbrain pathology in the CNS of LAMP-2-deficient mice (2015)
  • Author(s): Furuta A, Kikuchi H, Fujita H, Yamada D, Fujiwara Y, Kabuta T, Nishino I, Wada K, Uchiyama Y
  • Journal Title: Am J Pathol Volume: 巻未定
  • Peer Reviewed
• [Journal Article] Direct uptake and degradation of DNA by lysosomes (2013)
  • Author(s): Fujiwara Y, Kikuchi H, Aizawa S, Furuta A, Hatanaka Y, Konya C, Uchida K, Wada K, Kabuta T
  • Journal Title: Autophagy Volume: 9 Issue: 8 Pages: 1167-71
  • DOI: 10.4161/auto.24880
  • Peer Reviewed
• [Journal Article] Ubiquitin C-terminal hydrolase L1 (UCH-L1) act as a novel potentiator of cyclin-dependent kinases to enhance cell proliferation, independent of its hydrolase activity (2013)
  • Author(s): Kabuta, T., Mitsui, T., Takahashi, M., Fujiwara, Y., Kabuta, C., Konya, C., Tsuchiya, Y., Hatanaka, Y., Uchida, K., Hohjoh, H., Wada, K
  • Journal Title: J. Biol. Chem Volume: 288 Issue: 18 Pages: 12615-12626
  • DOI: 10.1074/jbc.m112.435701
  • Peer Reviewed
• [Journal Article] The AP-1 complex regulates intracellular localization of insulin receptor substrate 1, which is required for insulin-like growth factor I-dependent cell proliferation (2013)
  • Author(s): Yosuke Yoneyama
  • Journal Title: Molecular and Cellular Biology Volume: Volume 33 Issue: 10 Pages: 1991-2003
  • DOI: 10.1128/mcb.01394-12
  • Peer Reviewed
• [Journal Article] TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress (2013)
  • Author(s): Higashi S., Kabuta T., Nagai Y., Tsuchiya Y., Akiyama H., Wada K
  • Journal Title: J. Neurochem Volume: 126(2) Issue: 2 Pages: 288-300
  • DOI: 10.1111/jnc.12194
  • Peer Reviewed
• [Journal Article] Discovery of a novel type of autophagy targeting RNA (2013)
  • Author(s): Fujiwara Y, Furuta A, Kikuchi H, Aizawa S, Hatanaka Y, Konya C, Uchida K, Yoshimura A, Tamai Y, Wada K, Kabuta T
  • Journal Title: Autophagy Volume: 9 Issue: 3 Pages: 403-9
  • DOI: 10.4161/auto.23002
  • Peer Reviewed
• [Journal Article] Lysosomal storage and advanced senescence in the brain of LAMP-2-deficient Danon disease (2013)
  • Author(s): Furuta A, Wakabayashi K, Haratake J, Kikuchi H, Kabuta T, Mori F, Tokonami F, Katsumi Y, Tanioka F, Uchiyama Y, Nishino I, Wada K
  • Journal Title: Acta Neuropathol Volume: 125 Issue: 3 Pages: 459-461
  • DOI: 10.1007/s00401-012-1075-4
  • Peer Reviewed
• [Journal Article] Guideline for the use and interpretation of assays for monitoring autophagy (2012)
  • Author(s): Klionsky DJ,et al
  • Journal Title: Autophagy Volume: 8 Issue: 4 Pages: 445-544
  • DOI: 10.4161/auto.19496
  • Peer Reviewed
• [Journal Article] A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development. (2012)
  • Author(s): Morita M, Ler LW, Fabian MR, Siddiqui N, Mullin M, Henderson VC, Alain T, Fonseca BD, Karashchuk G, Bennett CF, Kabuta T, Higashi S, Larsson O, Topisirovic I, Smith RJ, Gingras AC, Sonenberg N.
  • Journal Title: Mol Cell Biol Volume: 32 Issue: 17 Pages: 3585-3593
  • DOI: 10.1128/mcb.00455-12
  • Peer Reviewed
• [Presentation] RNautophagy/DNautophagyのメカニズム (2015)
  • Author(s): 株田智弘
  • Organizer: 第67回日本細胞生物学会大会
  • Place of Presentation: タワーホール船堀（東京）
  • Year and Date: 2015-06-30
  • Invited
• [Presentation] Direct uptake and degradation of RNA/DNA by lysosomes (2014)
  • Author(s): Kabuta T
  • Organizer: The 16th Norteastern Asian Symposium on Autophagy
  • Place of Presentation: The Westin Chosun Busan Hotel, Busan, Republic of Korea
  • Year and Date: 2014-12-18 – 2014-12-21
  • Invited
• [Presentation] RNautophagy/DNautophagyの分子メカニズム (2014)
  • Author(s): 株田智弘
  • Organizer: 第8回オートファジー研究会・文部科学省科学研究費補助金「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
  • Place of Presentation: 札幌、シャトレーゼ ガトーキングダム サッポロ
  • Year and Date: 2014-11-09 – 2014-11-11
• [Presentation] A Novel Type of autophagy targeting RNA and its possible involvement in Danon disease (2014)
  • Author(s): Kabuta T
  • Organizer: Max Planck Institute & National Center of Neurology and Psychiatry Joint Symposium
  • Place of Presentation: The Prince Hakone, Hakone
  • Year and Date: 2014-11-05 – 2014-11-07
  • Invited
• [Presentation] リソソームにおける新たな核酸分解システム (2014)
  • Author(s): 株田智弘
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都、国立京都国際会館
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] 精神疾患の病因に関与する物質・因子の解析：テストステロンおよびリソソーム分解との関連性について (2014)
  • Author(s): 株田智弘, 畑中悠佑, 和田圭司
  • Organizer: 第36回日本生物学的精神医学会・第57回日本神経化学会合同年会
  • Place of Presentation: 奈良、奈良県新公会堂
  • Year and Date: 2014-09-29 – 2014-10-01
  • Invited
• [Presentation] 新たなオートファジーシステムRNautophagyの発見とそのメカニズム (2014)
  • Author(s): 株田智弘
  • Organizer: 大阪大学蛋白質研究所セミナー オートファジーと疾患
  • Place of Presentation: 大阪、大阪大学蛋白質研究所
  • Invited
• [Presentation] Discovery of Novel RNA/DNA degradation systems (2014)
  • Author(s): Fujiwara Y, Wada K, Kabuta T
  • Organizer: New Frontier of Molecular Neuropathology 2014
  • Place of Presentation: Tokyo, Tokyo Medical and Dental University, M&D Tower
• [Presentation] A Novel Type of Autophagy that Targets RNA. Keystone Symposia on Molecular and Cellular Biology (2013)
  • Author(s): Fuji war a Y, Furuta A, Kikuchi H, Aizawa S, Hatanaka Y, Konya C, Uchida K, Wada K, Kabuta T.
  • Organizer: Keystone Symposia on Molecular and Cellular Biology, Autophagy, Inflammation and Immunity
  • Place of Presentation: Fairmont The Queen Elizabeth Montreal, Canada
  • Year and Date: 2013-02-18
• [Presentation] 新規核酸分解システムRNautophagy/DNautophagy (2013)
  • Author(s): 株田智弘
  • Organizer: 第7回オートファジー研究会
  • Place of Presentation: 静岡、ヤマハリゾートつま恋カンファレンスセンター
• [Presentation] 脳におけるRNAを標的とした新規オートファジー経路 (2013)
  • Author(s): 藤原悠紀, 和田圭司, 株田智弘
  • Organizer: Neuro2013
  • Place of Presentation: 京都、京都国際会館
  • Invited
• [Presentation] Direct Uptake and Degradation of RNA by Lysosomes (2013)
  • Author(s): Fujiwara Y, Wada K, Kabuta T
  • Organizer: EMBO Conference: Autophagy: molecular mechanism, physiology and pathology
  • Place of Presentation: Norway, Hurtigruten MS Trollfjord
• [Presentation] RNAを標的とする新たなオートファジー機構 (2012)
  • Author(s): 藤原悠紀, 古田晶子, 菊地寿枝, 相澤修, 畑中悠佑, 紺谷千穂, 内田健康, 和田圭司, 株田智弘
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2012-12-11
• [Book] Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging (2013)
  • Author(s): Kabuta T, Fujiwara Y, Wada K
  • Total Pages: 8
  • Publisher: Elsevier
• [Book] 生化学 (2013)
  • Author(s): 株田智弘、藤原悠紀、和田圭司
  • Total Pages: 10
  • Publisher: 日本生化学会
• [Remarks]
  • URL: http://www.ncnp.go.jp/nin/guide/r4/index.html
• [Patent(Industrial Property Rights)] 異常核酸分解誘導剤 (2015)
  • Inventor(s): 株田智弘, 藤原悠紀, 和田圭司, 相澤修, 長谷勝徳
  • Industrial Property Rights Holder: 国立精神・神経医療研究センター
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-10-09
  • Overseas
• [Patent(Industrial Property Rights)] 異常核酸分解誘導剤 (2014)
  • Inventor(s): 株田智弘, 藤原悠紀, 和田圭司, 相澤修, 長谷勝徳
  • Industrial Property Rights Holder: 国立精神・神経医療研究センター
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-209340
  • Filing Date: 2014-10-10