Pathogenic mechanisms of Cushing disease caused by gain-of-function USP8 mutations

• Project/Area Number: 15H04293
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: Komada Masayuki 東京工業大学, 科学技術創成研究院, 教授 (10225568)
• Research Collaborator: Fukushima Toshiaki ; Endo Akinori ; Kawaguchi Kohei
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: ユビキチン / 脱ユビキチン化酵素 / エンドサイトーシス / 受容体ダウンレギュレーション / 腫瘍 / クッシング病 / 脳下垂体 / ACTH / 遺伝子 / 蛋白質 / 酵素 / 細胞・組織 / シグナル伝達 / 医療・福祉 / 生理学 / 癌

Outline of Final Research Achievements

Cushing’s disease, one of intractable diseases, is caused by the hypersecretion of adrenocorticotropic hormone (ACTH) from pituitary tumors. In this study, we showed that the gene encoding deubiquitinating enzyme USP8 is frequently mutated in the pituitary tumors of Japanese Cushing’s disease patients. Mechanistically, the mutation induces the increased interaction of USP8 with ubiquitin-binding protein STAM, thereby enhancing USP8 enzyme activity. The mutated form of USP8 excessively deubiquitinates some membrane proteins including EGF receptor, vasopressin receptor V1b and somatostatin receptor SSTR2/5, and affects corticotroph proliferation and hormone secretion.

Academic Significance and Societal Importance of the Research Achievements

日本人Cushing病患者で高頻度にUSP8遺伝子に変異が起きているという今回の研究結果は、USP8変異によるCushing病の発症機構の詳細な解析が、わが国におけるCushing病の治療法を確立する上で非常に重要であることを示すものである。また、USP8の遺伝子変異がACTH産生細胞の増殖やホルモン産生に影響する分子メカニズムの一部が明らかとなったことは、未だに特効薬のないCushing病の治療にとって、治療薬開発のための分子基盤を示した成果だと言える。従って、本研究成果は、Cushing病の発症メカニズムの解明に貢献しただけではなく、治療薬開発にも役立つと考えられ、社会的意義は非常に高い。

Research Products

• [Int'l Joint Research] カロリンスカ研究所/Lund大学(スウェーデン)
• [Int'l Joint Research] 応用科学アッパーオーストリア大学(オーストリア)
• [Int'l Joint Research] モナシュ大学(オーストラリア)
• [Int'l Joint Research] Medizinische Klinik und Poliklinik IV(ドイツ)
• [Int'l Joint Research] National Institute of Health(米国)
• [Int'l Joint Research] McGill University(カナダ)
• [Int'l Joint Research] University of Rome Tor Vergata(イタリア)
• [Int'l Joint Research] The University of Melbourne(オーストラリア)
• [Int'l Joint Research]
• [Int'l Joint Research] Medizinische Klinik und Poliklinik IV/Ludwig-Maximilians-Universitat Munchen/Max Planck Institute of Psychiatry(ドイツ)
• [Int'l Joint Research] National Institutes of Health/Oregon Health & Science University(米国)
• [Int'l Joint Research] Queen Mary University of London(英国)
• [Int'l Joint Research] Universite Paris Descartes(フランス)
• [Int'l Joint Research] Jiangsu Cancer Hospital(中国)
• [Int'l Joint Research]
• [Journal Article] RNA-seq of Isolated Chromaffin Cells Highlights the Role of Sex-Linked and Imprinted Genes in Adrenal Medulla Development. (2019)
  • Author(s): Chan Wing Hei, Komada Masayuki, Fukushima Toshiaki, Southard-Smith E. Michelle, Anderson Colin R., Wakefield Matthew J.
  • Journal Title: Scientific Report Volume: 9(1) Issue: 1 Pages: 3929-3929
  • DOI: 10.1038/s41598-019-40501-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The integral function of the endocytic recycling compartment is regulated by RFFL-mediated ubiquitylation of Rab11 effectors (2019)
  • Author(s): Sakai R, Fukuda R, Unida S, Aki M, Ono Y, Endo A, Kusumi S, Koga D, Fukushima T, Komada M, Okiyoneda T
  • Journal Title: J Cell Sci. Volume: 132 Issue: 3 Pages: 228007-228007
  • DOI: 10.1242/jcs.228007
  • Peer Reviewed
• [Journal Article] Ubiquitin-specific protease 8 deubiquitinates Sec31A and decreases large COPII carriers and collagen IV secretion (2018)
  • Author(s): Kawaguchi Kohei、Endo Akinori、Fukushima Toshiaki、Madoka Yuka、Tanaka Toshiaki、Komada Masayuki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 499 Issue: 3 Pages: 635-641
  • DOI: 10.1016/j.bbrc.2018.03.202
  • Peer Reviewed
• [Journal Article] IRS-2 deubiquitination by USP9X maintains anchorage-independent cell growth via Erk1/2 activation in prostate carcinoma cell line. (2018)
  • Author(s): Furuta Haruka, Yoshihara Hidehito, Fukushima Toshiaki, Yoneyama Yosuke, Ito Akihiro, Worrall Claire, Girnita Ada, Girnita Leonard, Yoshida Minoru, Asano Tomoichiro, Komada Masayuki, Kataoka Naoyuki, Chida Kazuhiro, Hakuno Fumihiko, Takahashi Shin-Ichiro
  • Journal Title: Oncotarget Volume: 9(74) Issue: 74 Pages: 33871-33883
  • DOI: 10.18632/oncotarget.26049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination. (2017)
  • Author(s): Fukushima T, Yoshihara H, Furuta H, Hakuno F, Iemura SI, Natsume T, Nakatsu Y, Kamata H, Asano T, Komada M, Takahashi SI.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 484 Issue: 3 Pages: 522-528
  • DOI: 10.1016/j.bbrc.2017.01.101
  • Peer Reviewed / Open Access
• [Journal Article] Tandem UIMs confer Lys48 ubiquitin chain substrate preference to deubiquitinase USP25 (2017)
  • Author(s): Kawaguchi K, Uo K, Tanaka T, Komada M
  • Journal Title: Sci. Rep. Volume: 7 Issue: 1 Pages: 45037-45037
  • DOI: 10.1038/srep45037
  • NAID: 120006605589
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Deficiency of X-linked protein kinase Nrk during pregnancy triggers breast tumor in mice (2016)
  • Author(s): Yanagawa T, Denda K, Inatani T, Fukushima T, Tanaka T, Kumaki N, Inagaki Y, Komada M
  • Journal Title: Am. J. Pathol. Volume: 186 Issue: 10 Pages: 2751-2760
  • DOI: 10.1016/j.ajpath.2016.06.005
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Ankrd13 family of ubiquitin-interacting motif-bearing proteins regulates VCP/p97-mediated lysosomal traffic of caveolin-1. (2016)
  • Author(s): Burana, D., Yoshihara, H., Tanno, H., Yamamoto, A., Saeki, Y., Tanaka, K., and Komada, M.
  • Journal Title: J. Biol. Chem. Volume: 291 Issue: 12 Pages: 6218-6231
  • DOI: 10.1074/jbc.m115.710707
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease. (2016)
  • Author(s): Hayashi, K., Inoshita, N., Kawaguchi, K., Ardisasmita, A.I., Suzuki, H., Fukuhara, N., Okada, M., Nishioka, H., Takeuchi, Y., Komada, M., Takeshita, A., and Yamada, S.
  • Journal Title: Eur. J. Endocrinol. Volume: 174 Issue: 2 Pages: 213-226
  • DOI: 10.1530/eje-15-0689
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] クッシング病の原因遺伝子と発症機構. (2016)
  • Author(s): 川口紘平、駒田雅之
  • Journal Title: Annual Review 糖尿病・代謝・内分泌 Volume: なし Pages: 180-186
• [Journal Article] 脱ユビキチン化酵素によるエンドサイトーシス制御と遺伝子疾患. (2016)
  • Author(s): 川口紘平、駒田雅之
  • Journal Title: 医学のあゆみ Volume: 256 Pages: 861-867
• [Journal Article] The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushing's disease. (2015)
  • Author(s): Perez-Rivas, L.G.,
  • Journal Title: J. Clin. Endocrinol. Metab. Volume: 100 Issue: 7 Pages: E997-E1004
  • DOI: 10.1210/jc.2015-1453
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Decoding the genetic basis of Cushing's disease: USP8 in the spotlight. (2015)
  • Author(s): Theodoropoulou, M., Reincke, M., Fassnacht, M., and *Komada, M. (*co-correspondence)
  • Journal Title: Eur. J. Endocrinol. Volume: 173 Issue: 4 Pages: M73-M83
  • DOI: 10.1530/eje-15-0320
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc (2015)
  • Author(s): Sun XX, He X, Yin L, Komada M, Sears RC & Dai MS
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 112 Issue: 12 Pages: 3734-3739
  • DOI: 10.1073/pnas.1411713112
  • Peer Reviewed / Open Access
• [Journal Article] 脱ユビキチン化酵素USP8の機能獲得型変異はCushing病をひき起こす (2015)
  • Author(s): 駒田 雅之
  • Journal Title: ライフサイエンス新着論文レビュー ”First Author's" Volume: なし
• [Journal Article] 見えてきたユビキチンを介した核小体の多彩な機能 (2015)
  • Author(s): 川口 紘平、駒田 雅之
  • Journal Title: ファルマシア Volume: 51 Pages: 300-304
• [Journal Article] 難病 ”クッシング病” 発症の分子メカニズム. (2015)
  • Author(s): 川口 紘平、駒田 雅之
  • Journal Title: バイオサイエンスとインダストリー Volume: 73 Pages: 300-301
• [Journal Article] 脱ユビキチン化酵素USP8変異とCushing病 (2015)
  • Author(s): 駒田 雅之
  • Journal Title: クッシング症候群診療マニュアル Volume: なし Pages: 259-260
• [Journal Article] 脱ユビキチン化酵素USP8の機能獲得型変異がクッシング病を引き起こす (2015)
  • Author(s): 駒田 雅之
  • Journal Title: ACTH Related Peptides Volume: 26 Pages: 56-58
• [Presentation] 脱ユビキチン化酵素USP8の自己活性抑制機構 (2019)
  • Author(s): 柿原慧遵、 浅水謙吾、 遠藤彬則、 駒田雅之、福嶋俊明
  • Organizer: 第2回ユビキチン研究会
• [Presentation] Nuclear localization mechanism of deubiquitinating enzyme USP8 in Cushing’s disease. (2018)
  • Author(s): Takahiro Sawada, Kazuya Inoko, Kohei Kawaguchi, Akinori Endo, Yasushi Saeki, Keiji Tanaka, Toshiaki Fukushima, Masayuki Komada
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Molecular mechanisms underlying the control of Nrk protein levels and Nrk-mediated anti-proliferation effects. (2018)
  • Author(s): Satomi Naito, Akinori Endo, Toshiaki Fukushima, Kimitoshi Denda, Akira Kato, Masayuki Komada
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] A deubiquitinase USP8, a master regulator of endosome-centered membrane traffic, controls inter-cellular signal transduction. (2018)
  • Author(s): Akinori Endo, Toshiaki Fukushima, Masayuki Komada
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] USP8 遺伝子のゲノム編集によるCushing 病モデル細胞の作製と解析 (2018)
  • Author(s): Suguru Machidori, Kazuya Inoko, Kohei Kawaguchi, Akinori Endo, Toshiaki Fukushima, Masayuki Komada
  • Organizer: 第33回日本下垂体研究会学術集会
• [Presentation] Ubiquitin-specific protease 8 suppresses collagen secretion by deubiquitinating Sec31. (2018)
  • Author(s): Kohei Kawaguchi, Akinori Endo, Toshiaki Fukushima, Masayuki Komada
  • Organizer: Cell and Developmental Biology Meeting
• [Presentation] Deubiquitinases USP5 and USP13 are recruited to and regulate heat-induced stress granules by deubiquitinating activities. (2018)
  • Author(s): Xie Xuan, Shunsuke Matsumoto, Akinori Endo, Toshiaki Fukushima, Hiroyuki Kawahara, Yasushi Saeki, Masayuki Komada
  • Organizer: Cold Spring Harbor Asia Conferences, Ubiquitin Family, Autophagy and Diseases,
  • Int'l Joint Research
• [Presentation] クッシング病において脱ユビキチン化酵素USP8変異体を活性化するプロテアーゼの解析 (2017)
  • Author(s): 浅水謙吾、川口紘平、遠藤彬則、福嶋俊明、金丸周司、駒田雅之
  • Organizer: 第28回 間脳・下垂体・副腎系研究会
  • Place of Presentation: ロシュ・ダイアグノスティックス 本社ビル（東京都港区）
• [Presentation] 遺伝子変異による脱ユビキチン化酵素USP8の細胞質から核への局在変化とCushing病 (2016)
  • Author(s): 駒田雅之
  • Organizer: 第39回 日本分子生物学会大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] 母性Cyclin E-DNMT1新規複合体によるツメガエル尾部形成のエピジェネティックな制御 (2016)
  • Author(s): 田中利明、駒田雅之
  • Organizer: 第39回 日本分子生物学会大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] クッシング病で見られる脱ユビキチン化酵素USP8の変異はバソプレシン受容体V1bの安定化を引き起こす (2016)
  • Author(s): 福嶋俊明、川口紘平、遠藤彬則、駒田雅之
  • Organizer: 第39回 日本分子生物学会大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] 脱ユビキチン化酵素USP28はSnailを安定化し、がん細胞の浸潤に寄与する (2016)
  • Author(s): 佐藤晃一、井上靖道、伊藤友香、駒田雅之、林秀敏
  • Organizer: 第39回 日本分子生物学会大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] Deubiquitinase USP5 is required for the disassembly of heat-induced stress granules (2016)
  • Author(s): Xuan Xie, Shunsuke Matsumoto, Masayuki Komada
  • Organizer: 第39回 日本分子生物学会大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] 脱ユビキチン化酵素USP25のユビキチン結合モチーフはK48ユビキチン鎖に対する切断特異性を規定する (2016)
  • Author(s): 川口紘平、卯尾和音、田中利明、駒田雅之
  • Organizer: 第39回 日本分子生物学会大会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] Cushing病におけるUSP8インタラクトーム解析 (2016)
  • Author(s): 駒田雅之
  • Organizer: 第43回 日本神経内分泌学会学術集会
  • Place of Presentation: アクトシティ浜松コングレスセンター（静岡県浜松市）
  • Year and Date: 2016-10-14
  • Invited
• [Presentation] USP8 interactome in Cushing’s disease (2016)
  • Author(s): Masayuki Komada
  • Organizer: IMPROCUSH-2 (Improving Outcome of Cushing’s Syndrome Symposium 2)
  • Place of Presentation: Carl Friedrich von Siemens Stiftung (Munich, Germany)
  • Year and Date: 2016-06-23
  • Int'l Joint Research / Invited
• [Presentation] 脱ユビキチン化酵素USP25におけるユビキチン結合モチーフUIMの機能 (2015)
  • Author(s): 卯尾和音、田中利明、駒田雅之
  • Organizer: 第38回 日本分子生物学会/第88回日本生化学会・合同大会 BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-02
• [Presentation] 脱ユビキチン化酵素USP37におけるユビキチン結合モチーフUIMの機能 (2015)
  • Author(s): 西川周平、桑原直之、伝田公紀、川崎政人、駒田雅之、加藤龍一
  • Organizer: 第38回 日本分子生物学会/第88回 日本生化学会・合同大会 BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-02
• [Presentation] 脳下垂体の腫瘍性疾患クッシング病における脱ユビキチン化酵素USP8の活性化変異 (2015)
  • Author(s): 駒田雅之、川口紘平、Arif Ibrahim Ardisasmita、福嶋俊明
  • Organizer: 第38回 日本分子生物学会/第88回 日本生化学会・合同大会 BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] Somatic gain-of-function mutations in deubiquitinase USP8 in pituitary tumors causing Cushing's disease (2015)
  • Author(s): 駒田雅之
  • Organizer: EMBO Conference on “Ubiquitin and Ub-like modifiers”
  • Place of Presentation: Hotel Croatia（クロアチア・ツァブタット）
  • Year and Date: 2015-09-19
  • Int'l Joint Research
• [Book] Encyclopedia of Signaling Molecules, 2nd Edition (2017)
  • Author(s): Komada M, Reincke M, Theodoropoulou M
  • Total Pages: 4700
  • Publisher: Springer
• [Remarks] 東京工業大学 科学技術創成研究院 細胞制御工学研究センター 駒田研究室
  • URL: https://komada-lab.jimdo.com/
• [Remarks] 駒田研究室 ホームページ
  • URL: http://www.komada-lab.bio.titech.ac.jp
• [Remarks] 細胞制御工学研究センター ホームページ
  • URL: http://www.rcb.iir.titech.ac.jp
• [Remarks] 科学技術創成研究院 ホームページ
  • URL: http://www.iir.titech.ac.jp
• [Remarks] 生命理工学院 ホームページ
  • URL: http://www.educ.titech.ac.jp/bio/
• [Remarks] 東京工業大学 ホームページ
  • URL: http://www.titech.ac.jp
• [Remarks] 東京工業大学 科学技術創成研究院 駒田研究室 ホームページ
  • URL: http://www.komada-lab.bio.titech.ac.jp
• [Remarks] 科研費 新学術領域 ユビキチン制御 ホームページ
  • URL: http://www.ubiquitin.jp