Molecular understanding of osmotic stress sensing and response

• Project/Area Number: 18H03995
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: ICHIJO HIDENORI 東京大学, 大学院薬学系研究科(薬学部), 教授 (00242206)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥44,460,000 (Direct Cost: ¥34,200,000、Indirect Cost: ¥10,260,000); Fiscal Year 2020: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000); Fiscal Year 2019: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000); Fiscal Year 2018: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
• Keywords: ASK3 / 浸透圧ストレス受容 / 浸透圧ストレス応答 / 細胞体積制御 / VRAC/LRRC8 / アポトーシス / 液―液相分離 / ポリADPリボース / 浸透圧受容 / 浸透圧応答 / 細胞体積

Outline of Final Research Achievements

Cells are constantly exposed to osmotic stress that forces them to change their volume due to osmotic pressure differences between the inside and outside of the cell, so called osmotic stress, and they maintain a constant volume by sensing osmotic pressure changes and responding appropriately. Until now, most studies have been based on the idea that osmotic changes without physical substance are sensed through changes in the cell membrane, which is in contact with the extracellular environment.
Using the ASK3 protein as a research model, we have elucidated that cells sense osmotic stress internally using the physical phenomenon of liquid-liquid phase separation as a "trigger". These are the results of taking advantage of molecular biological and biochemical methods and computer simulations.

Academic Significance and Societal Importance of the Research Achievements

本研究はいわゆる基礎研究に相当しますが、本研究成果によってASK3の役割から期待される高血圧疾患や浮腫などに対する新規治療薬の開発に向けて前進しました。さらに本研究成果によって得られた知見を活かして液―液相分離を積極的に操作することで、神経変性疾患など多くの疾患に対する新規治療戦略の開発に発展することも期待されます。

Research Products

• [Journal Article] Cells recognize osmotic stress through liquid-liquid phase separation lubricated with poly(ADP-ribose) (2021)
  • Author(s): Watanabe Kengo、Morishita Kazuhiro、Zhou Xiangyu、Shiizaki Shigeru、Uchiyama Yasuo、Koike Masato、Naguro Isao、Ichijo Hidenori
  • Journal Title: Nat. Commun. Volume: 12 Pages: 1353-1353
  • DOI: 10.1038/s41467-021-21614-5
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Lens for Cell Volume Regulation: Liquid-Liquid Phase Separation (2021)
  • Author(s): Ishihara, S., Ichijo, H., Watanabe, K.
  • Journal Title: Cellular Physiology and Biochemistry Volume: 55 Pages: 135-160
  • DOI: 10.33594/000000357
  • Peer Reviewed / Open Access
• [Journal Article] The mitochondrial Ca2+ uptake regulator, MICU1, is involved in cold stress‐induced ferroptosis (2021)
  • Author(s): Nakamura Toshitaka、Ogawa Motoyuki、Kojima Kazuki、Takayanagi Saki、Ishihara Shunya、Hattori Kazuki、Naguro Isao、Ichijo Hidenori
  • Journal Title: EMBO Rep. Volume: 22
  • DOI: 10.15252/embr.202051532
  • Peer Reviewed / Open Access
• [Journal Article] ASK1 suppresses NK cell-mediated intravascular tumor cell clearance in lung metastasis. (2021)
  • Author(s): Fujimoto, M., Kamiyama, M., Fuse, K., Ryuno, H., Odawara, T., Furukawa, N., Yoshimatsu, Y., Watabe, T., Michaela, P.-M., Veronika, S., Tahara, H., Hayakawa, Y., Sato, T., Takeda, K., Naguro, I. and Ichijo, H.
  • Journal Title: Cancer Sci. Volume: 112 Pages: 1633-1643
  • DOI: 10.1111/cas.14842
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FGF21 Induced by the ASK1-p38 Pathway Promotes Mechanical Cell Competition by Attracting Cells (2021)
  • Author(s): Ogawa Motoyuki、Kawarazaki Yosuke、Fujita Yasuyuki、Naguro Isao、Ichijo Hidenori
  • Journal Title: Curr. Biol. Volume: 31 Pages: 1048-1057
  • DOI: 10.1016/j.cub.2020.11.052
  • Peer Reviewed / Open Access
• [Journal Article] Molecular functions of ASK family in diseases caused by stress-induced inflammation and apoptosis (2021)
  • Author(s): Kojima Kazuki、Ichijo Hidenori、Naguro Isao
  • Journal Title: J. Biochem. Volume: in press Pages: 395-407
  • DOI: 10.1093/jb/mvaa145
  • NAID: 40022588047
  • Peer Reviewed
• [Journal Article] The CCR4-NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression (2020)
  • Author(s): Ito-Kureha Taku、Miyao Takahisa、Nishijima Saori、Suzuki Toru、Koizumi Shin-ichi、Villar-Briones Alejandro、Takahashi Akinori、Akiyama Nobuko、Morita Masahiro、Naguro Isao、Ishikawa Hiroki、Ichijo Hidenori、Akiyama Taishin、Yamamoto Tadashi
  • Journal Title: Nature Communications Volume: 11 Pages: 6169-6169
  • DOI: 10.1038/s41467-020-19975-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes (2020)
  • Author(s): Hattori Kazuki、Wakatsuki Hiroaki、Sakauchi Chihiro、Furutani Shotaro、Sugawara Sho、Hatta Tomohisa、Natsume Tohru、Ichijo Hidenori
  • Journal Title: PLOS ONE Volume: 15
  • DOI: 10.1371/journal.pone.0232645
  • Peer Reviewed / Open Access
• [Journal Article] Apoptosis signal-regulating kinase 1 (ASK1) as a therapeutic target for neurological diseases (2020)
  • Author(s): Takenaka Satoshi、Fujisawa Takao、Ichijo Hidenori
  • Journal Title: Expert Opinion on Therapeutic Targets Volume: 24 Pages: 1061-1064
  • DOI: 10.1080/14728222.2020.1821648
  • Peer Reviewed
• [Journal Article] Cryo-EM structure of the volume-regulated anion channel LRRC8D isoform identifies features important for substrate permeation (2020)
  • Author(s): Nakamura Ryoki、Numata Tomohiro、Kasuya Go、Yokoyama Takeshi、Nishizawa Tomohiro、Kusakizako Tsukasa、Kato Takafumi、Hagino Tatsuya、Dohmae Naoshi、Inoue Masato、Watanabe Kengo、Ichijo Hidenori、Kikkawa Masahide、Shirouzu Mikako、Jentsch Thomas J.、Ishitani Ryuichiro、Okada Yasunobu、Nureki Osamu
  • Journal Title: Commun. Biol. Volume: 3 Pages: 240-240
  • DOI: 10.1038/s42003-020-0951-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1. (2020)
  • Author(s): Sugawara, S., Kanamaru, Y., Sekine, S., Maekawa, L., Takahashi, A., Yamamoto, T., Watanabe, K., Fujisawa, T., Hattori, K. and Ichijo, H.
  • Journal Title: Journal of Biological Chemistry Volume: 295 Pages: 5588-5601
  • DOI: 10.1074/jbc.ra119.011508
  • Peer Reviewed / Open Access
• [Journal Article] ASK1 promotes uterine inflammation leading to pathological preterm birth (2020)
  • Author(s): Yoshikawa Midori、Iriyama Takayuki、Suzuki Kensuke、Sayama Seisuke、Tsuruga Tetsushi、Kumasawa Keiichi、Nagamatsu Takeshi、Homma Kengo、Naguro Isao、Osuga Yutaka、Ichijo Hidenori、Fujii Tomoyuki
  • Journal Title: Sci. Rep. Volume: 10 Pages: 1887-1887
  • DOI: 10.1038/s41598-020-58653-9
  • 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 Pages: 201900576-201900576
  • DOI: 10.26508/lsa.201900576
  • NAID: 120006980545
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu/Zn superoxide dismutase. (2020)
  • Author(s): Homma, K., Takahashi, H., Tsuburaya, N., Naguro, I., Fujisawa, T. and Ichijo, H.
  • Journal Title: Journal of Biological Chemistry Volume: 295 Pages: 3148-3158
  • DOI: 10.1074/jbc.ra119.010239
  • Peer Reviewed / Open Access
• [Journal Article] Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases. (2019)
  • Author(s): Nakamura, T., Naguro, I. and Ichijo, H.
  • Journal Title: Biochimica et Biophysica Acta (BBA) - General Subjects Volume: pii Pages: 1398-1409
  • DOI: 10.1016/j.bbagen.2019.06.010
  • Peer Reviewed
• [Journal Article] Cell volume regulation in cancer cell migration driven by osmotic water flow (2019)
  • Author(s): Morishita Kazuhiro、Watanabe Kengo、Ichijo Hidenori
  • Journal Title: Cancer Science Volume: 110 Pages: 2337-2347
  • DOI: 10.1111/cas.14079
  • Peer Reviewed / Open Access
• [Journal Article] β-TrCP-dependent degradation of ASK1 suppresses the induction of the apoptotic response by oxidative stress (2018)
  • Author(s): Cheng Ran、Takeda Kohsuke、Naguro Isao、Hatta Tomohisa、Iemura Shun-ichiro、Natsume Tohru、Ichijo Hidenori、Hattori Kazuki
  • Journal Title: Biochim. Biophys. Acta, Volume: 1862 Pages: 2271-2280
  • DOI: 10.1016/j.bbagen.2018.07.015
  • Peer Reviewed
• [Journal Article] A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model (2018)
  • Author(s): Tsuburaya, N., Homma, K., Higuchi, T., Balia, A., Yamakoshi, H., Shibata, N., Nakamura, S., Nakagawa, H., Ikeda, S., Umezawa, N., Kato, N., Yokoshima, S., Shibuya, M., Shimonishi, M., Kojima, H., Okabe, T., Nagano, T., Naguro, I., Imamura, K., Inoue, H., Fujisawa, T., and Ichijo, H.
  • Journal Title: Nat Commun Volume: 9 Pages: 1-12
  • DOI: 10.1038/s41467-018-05127-2
  • NAID: 120006546002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cryo-EM structure of the volume-regulated anion channel LRRC8 (2018)
  • Author(s): Kasuya Go、Nakane Takanori、Yokoyama Takeshi、Jia Yanyan、Inoue Masato、Watanabe Kengo、Nakamura Ryoki、Nishizawa Tomohiro、Kusakizako Tsukasa、Tsutsumi Akihisa、Yanagisawa Haruaki、Dohmae Naoshi、Hattori Motoyuki、Ichijo Hidenori、Yan Zhiqiang、Kikkawa Masahide、Shirouzu Mikako、Ishitani Ryuichiro、Nureki Osamu
  • Journal Title: Nat. Struct. Mol. Biol. Volume: 25 Pages: 797-804
  • DOI: 10.1101/331207
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ASK family kinases mediate cellular stress and redox signaling to circadian clock (2018)
  • Author(s): Imamura Kiyomichi、Yoshitane Hikari、Hattori Kazuki、Yamaguchi Mitsuo、Yoshida Kento、Okubo Takenori、Naguro Isao、Ichijo Hidenori、Fukada Yoshitaka
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 115 Pages: 3646-3651
  • DOI: 10.1073/pnas.1719298115
  • Peer Reviewed / Open Access
• [Journal Article] A PP6-ASK3 Module Coordinates the Bidirectional Cell Volume Regulation under Osmotic Stress (2018)
  • Author(s): Watanabe Kengo、Umeda Tsuyoshi、Niwa Kuniyoshi、Naguro Isao、Ichijo Hidenori
  • Journal Title: Cell Rep. Volume: 22 Pages: 2809-2817
  • DOI: 10.1016/j.celrep.2018.02.045
  • Peer Reviewed / Open Access
• [Journal Article] Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. (2018)
  • Author(s): Galluzzi, L. et al.
  • Journal Title: Cell Death & Differentiation Volume: 25 Pages: 486-541
  • DOI: 10.1038/s41418-017-0012-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer’s Disease and Brain Aging (2018)
  • Author(s): Hasegawa Yu、Toyama Kensuke、Uekawa Ken、Ichijo Hidenori、Kim-Mitsuyama Shokei
  • Journal Title: Journal of Alzheimer's Disease Volume: 61 Pages: 259-263
  • DOI: 10.3233/jad-170645
  • Peer Reviewed / Open Access
• [Journal Article] mASKing cancer cells in a tumor microenvironment (2018)
  • Author(s): Kamiyama Miki、Naguro, Isao、Ichijo Hidenori
  • Journal Title: Cell Cycle Volume: 17 Pages: 139-140
  • DOI: 10.1080/15384101.2017.1407402
  • Peer Reviewed / Open Access
• [Journal Article] Apoptosis signal-regulating kinase 1 in regulated necrosis (2018)
  • Author(s): Hattori Kazuki、Ichijo Hidenori
  • Journal Title: Cell Cycle. Volume: 17 Pages: 1-2
  • DOI: 10.1080/15384101.2017.1397330
  • Peer Reviewed / Open Access
• [Presentation] TRPM4は細胞内液滴の流動性制御を介してASK3不活性化に寄与する (2020)
  • Author(s): 森下和浩、渡邊謙吾、名黒功、一條秀憲
  • Organizer: 若手ファーマバイオフォーラム2020
• [Presentation] 浸透圧ストレス応答と細胞死制御における体積調節の共通性 (2019)
  • Author(s): 井上雅斗、渡邊謙吾、一條秀憲
  • Organizer: 第28回日本Cell Death学会学術集会
• [Presentation] 相分離が高浸透圧ストレス下でのPP6によるASK3不活性化を制御する (2019)
  • Author(s): 渡邊謙吾、名黒功、一條秀憲
  • Organizer: 第92回日本生化学会大会
• [Presentation] ASK1はNOD-RIPK2経路を抑制し脂肪細胞での炎症応答を制御する (2019)
  • Author(s): 高柳早希、渡邊謙吾、一條秀憲
  • Organizer: 第92回日本生化学会大会
• [Presentation] ASK3不活性化における高浸透圧ストレスセンサー候補分子TRPM4の機能解析 (2019)
  • Author(s): 森下和浩、渡邊謙吾、一條秀憲
  • Organizer: 第92回日本生化学会大会
• [Presentation] ポリADPリボースは液－液相分離を介して浸透圧ストレス応答キナーゼASK3を制御する (2019)
  • Author(s): 渡邊謙吾、森下和浩、一條秀憲
  • Organizer: 第14回日本臨床ストレス応答学会大会
• [Presentation] ASK1はNOD-RIPK2経路を抑制し脂肪細胞での炎症応答を制御する (2019)
  • Author(s): 高柳早希、渡邊謙吾、一條秀憲
  • Organizer: 第14回日本臨床ストレス応答学会大会
• [Presentation] ASK3不活性化における高浸透圧ストレスセンサー候補分子TRPM4の機能解析 (2019)
  • Author(s): 森下和浩、渡邊謙吾、一條秀憲
  • Organizer: 第14回日本臨床ストレス応答学会大会
• [Presentation] ASK1はNOD-RIPK2経路を抑制し褐色脂肪細胞での炎症応答を制御する (2019)
  • Author(s): 高柳早希、渡邊謙吾、一條秀憲
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] ASK3不活性化における高浸透圧ストレスセンサー候補分子TRPM4の機能解析 (2019)
  • Author(s): 森下和浩、渡邊謙吾、石原駿弥、一條秀憲
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] ASK3 modulates cell volume under osmotic stress and beyond. (2018)
  • Author(s): 渡邊謙吾、一條秀憲
  • Organizer: 第10回シグナルネットワーク研究会
• [Presentation] ストレスシグナルによる神経変性制御 (2018)
  • Author(s): 一條秀憲
  • Organizer: 第41回日本神経科学大会
  • Invited
• [Presentation] ASK3による体積調節を介した細胞死制御 (2018)
  • Author(s): 井上雅斗、渡邊謙吾、一條秀憲
  • Organizer: 第91回日本生化学会大会
• [Presentation] ASK1はNOD-RIPK2経路を制御する (2018)
  • Author(s): 高柳早希、渡邊謙吾、一條秀憲
  • Organizer: 第91回日本生化学会大会
• [Presentation] プロテアソーム依存的なASK3の不活性化による高浸透圧ストレス応答の制御 (2018)
  • Author(s): 周翔宇、渡邊謙吾、森下和浩、名黒功、一條秀憲
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] ASK3による体積調節を介した細胞死制御 (2018)
  • Author(s): 井上雅斗、渡邊謙吾、一條秀憲
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] ASK3不活性化における高浸透圧ストレスセンサー候補分子TRPML1の機能解析 (2018)
  • Author(s): 森下和浩、渡邊謙吾、一條秀憲
  • Organizer: 第41回日本分子生物学会年会