Mechanism underlying selective substrate recognition by the ubiquitin system

2010 Fiscal Year Final Research Report

• Project Area: Proteolysis in the Regulation of Biological Processes
• Project/Area Number: 18076004
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University (2008-2010); Osaka City University (2006-2007)
• Principal Investigator: IWAI Kazuhiro Osaka University, 大学院・生命機能研究科, 教授 (60252459)
• Co-Investigator(Kenkyū-buntansha): KAWAHARA Hiroyuki 首都大学東京, 大学院・理工学研究科, 教授 (70291151) ; TOKUNAGA Fuminori 大阪大学, 大学院・医学系研究科, 准教授 (00212069)
• Project Period (FY): 2006 – 2010
• Keywords: タンパク質 / 分解 / ユビキチン

Research Abstract

The ubiquitin conjugation system regulates function of substrate proteins by conjugating ubiquitin in a selective manner. In this research projects, we have identified mechanisms underlying release of ubiquitinated substrate from ubiquitin ligases, which leads to degradation of the proteins and delivery of nascent abnormal proteins to the proteasome. We also identified regulation of cell functions by newly identified polyubiqutin chains.

Research Products

• [Journal Article] SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. (2011)
  • Author(s): Ikeda, F., Deribe, Y.L., Skanland, S.S., Stieglitz, B., Grabbe, C., Franz-Wachtel, M., van Wijk, S.J.L., Goswami, P., Nagy, V., Terzic, J., Tokunaga, F., Androulidaki, A., Nakagawa, T., Pasparakis, M., Iwai, K., Sundberg, J.P., Rittinger, K., Schaefer, L., Macek, B., Dikic, I.
  • Journal Title: Nature 471 Pages: 637-641
• [Journal Article] SHARPIN is a component of the NF-κB activating linear ubiquitin chain assembly complex. (2011)
  • Author(s): Tokunaga, F., Nakagawa, T., Nakahara, M., Saeki, Y., Taniguchi, M., Sakata, S.-I., Tanaka, K., Nakano, H., Iwai, K.
  • Journal Title: Nature 471 Pages: 633-636
• [Journal Article] Linear ubiquitin assembly complex negatively regulates RIG-I-and TRIM25-mediated type-I interferon induction. (2011)
  • Author(s): Inn, K.-S., Gack, M.U.Tokunaga, F., Shi, M., Wong, L.-Y., Iwai, K., (corresponding author) Jung, J.U.
  • Journal Title: Molecular Cell 41 Pages: 354-365
• [Journal Article] A novel signaling pathway mediated by the nuclear targeting of C-terminal fragments of mammalian Patched 1. (2011)
  • Author(s): Kagawa, H., Shino, Y., Kobayashi, D., Demizu, S., Shimada.M., Ariga, H.Kawahara, H.
  • Journal Title: PLoS ONE 6 Pages: e18638. doi:10.1371/journal.pone.0018638
• [Journal Article] BAG-6 is essential for selective elimination of defective proteasomal substrates. (2010)
  • Author(s): Minami, R., Hayakawa, A., Kagawa, H., Yanagi, Y., Yokosawa, H.Kawahara, H.
  • Journal Title: J.Cell Biol. 190 Pages: 637-650
• [Journal Article] Role of dynamic distribution of muscle-specific calpain in physical-stress adaptation and muscular dystrophy in mice. (2010)
  • Author(s): Ojima, K., Y Kawabata, Y., Nakao, H., Nakao, K., Doi, N., Kitamura, F., Ono, Y., Hata, S., Suzuki, H., Kawahara, H., Labeit, S., Toyama-Sorimachi, N., Suzuki, K., Maeda, T., Abe, K., Aiba, A.Sorimachi, H.
  • Journal Title: J.Clinc.Invest. 120 Pages: 2672-2683
• [Journal Article] Involvement of linear polyubiquitination of NEMO in NF-κB activation. (2009)
  • Author(s): Tokunaga, F., Sakata, S.-I., Saeki, Y., Satomi, Y., Kirisako, T., Kamei, K., Nakagawa, T., Kato, M., Murata, S., Yamaoka, S., Yamamoto, M., Akira, S., Takao, T., Tanaka, K.Iwai, K.
  • Journal Title: Nature Cell Biology 11 Pages: 123-132
• [Journal Article] Structural basis for specific cleavage of Lys63-linked polyubiquitin chains. (2008)
  • Author(s): Sato, Y., Yoshikawa, A., Yamagata, A., Mimura, H., Yamashita, M., Ookata, K., Nureki, O., Iwai, K., Komada, M., Fukai, S.
  • Journal Title: Nature 455 Pages: 358-362
• [Journal Article] The COP9/signalosome increases the efficiency of pVHL ubiquitin ligase.mediated hypoxia inducible factor-α ubiquitination. (2008)
  • Author(s): Miyauchi, Y., Kato, M., Tokunaga, F., Iwai, K.
  • Journal Title: J.Biol.Chem. 283 Pages: 16622-16631
• [Journal Article] Gp78 Cooperates with RMA1 in ER-associated Degradation of CFTRΔF508. (2008)
  • Author(s): Morito, D., Hirao, K., Oda, Y., Hosokawa, N., Tokunaga, F., Cyr, D.M., Tanaka, K., Iwai, K., Nagata K.
  • Journal Title: Mol.Biol.Cell. 19 Pages: 1328-1336
• [Journal Article] Hypoxia-mediated Na-K-ATPase degradation requires von Hippel Lindau protein. (2008)
  • Author(s): Zhou, G., Dada, L.A., Chandel, N.S., Iwai, K., Lecuona, E., Ciechanover, A., Sznajder, J.I.
  • Journal Title: FASEB J. 22 Pages: 1335-1342
• [Journal Article] Scythe regulates apoptosis through modulating ubiquitin-mediated proteolysis of XEF1AO. (2007)
  • Author(s): Minami, R., Shimada, M., Yokosawa, H.Kawahara, H.
  • Journal Title: Biochem.J.(London) 405 Pages: 495-501
• [Journal Article] Ubiquitin is degraded by the ubiquitin system as a monomer and as part of its conjugated target. (2007)
  • Author(s): Shabek, N., Iwai, K., Ciechanover, A.
  • Journal Title: Biochem Biophys Res Commun. 363 Pages: 425-431
• [Journal Article] Direct interactions between Nedd8 and uE2 conjugating enzymes contribute up-regulation of cullin-based E3 ligase activity. (2007)
  • Author(s): Sakata, E., Yamaguchi, Y., Miyauchi, Y., Iwai, K., Chiba, T., Saeki, Y., Matsuda, N., Tanaka, K.Kato, K.
  • Journal Title: Nature Struct.Mol.Biol. 14: Pages: 167-168
• [Journal Article] Proteasomal ubiquitin receptor RPN-10 controls sex determination in Caenorhabditis elegans. (2006)
  • Author(s): Shimada, M., Kanematsu, K., Tanaka, K., Yokosawa, H.Kawahara, H.
  • Journal Title: Mol.Biol.Cell 17 Pages: 5356-5371
• [Journal Article] A ubiquitin ligase complex assembles linear polyubiquitin chains. (2006)
  • Author(s): Kirisako, T., Kamei, K., Murata, S., Kato, M., Fukumoto, H., Kanie, K., Sano, S.Tokunaga, F., Tanaka, K.Iwai, K.
  • Journal Title: EMBO J. 25 Pages: 4877-4887
• [Presentation] Linear polyubiquitination : a new regulator of NF-κB signaling. (2010)
  • Author(s): Iwai, K.
  • Organizer: Banbury Center meetings,"SIGNALING THROUGH UBIQUITIN(Invited)
  • Place of Presentation: The Banbury Center, Cold Spring Harbor Laboratory, New York, USA.
  • Year and Date: 20101114-20101117
• [Presentation] Linear polyubiquitination : a new regulator of NF-κB signaling. (2010)
  • Author(s): Iwai, K.
  • Organizer: 2010 FASEB Summer Research Conferences "Ubiquitin and Cellular Regulation"(Invited)
  • Place of Presentation: Saxtons River, Vermont, USA.
  • Year and Date: 20100613-20100618
• [Presentation] Linear Polyubiquitination : A Newly Identified Regulator of NF-κB Signaling. (2010)
  • Author(s): Iwai, K.
  • Organizer: BIOLOGY OF THE UBIQUITIN AND THE UBIQUITIN-LIKE SYSTEMS Research Conference of the Institute for Advanced Studies, the Israel Science Foundation.(Invited)
  • Place of Presentation: Jerusalem, Israel.
  • Year and Date: 20100314-20100319
• [Presentation] Linear polyubiquitination : A newly identified regulator of NF-κB signaling. (2010)
  • Author(s): Iwai, K., Sakata, S.-I., Nakagawa, T., Tokunaga, F.
  • Organizer: Keystone Symposium "NF-κB in Inflammation and Disease"
  • Place of Presentation: Santa Fe, New Mexico, USA.
  • Year and Date: 20100110-20100115
• [Presentation] polyubiquitination : A newly identified regulator of NF-κB signaling. (2009)
  • Author(s): Iwai, K., Tokunaga, F.Linear
  • Organizer: The EMBO Conference "Ubiquitin and Ubiquitin-like Modifiers in Cellular Regulation"
  • Place of Presentation: Riva Del Garda, Italy.
  • Year and Date: 20090922-20090926
• [Presentation] Involvement of linear polyubiquitination of NEMO in NF-κB activation (2009)
  • Author(s): Tokunaga, F., Sakata, S.-I., Nakagawa, T., Iwai, K.
  • Organizer: Cold Spring Harbor Laboratory meeting "The Ubiquitin Family"
  • Place of Presentation: Cold Spring Harbor, NY, USA.
  • Year and Date: 20090421-20090425
• [Presentation] Physiological Function of Linear Polyubiquitin Chain. (2009)
  • Author(s): Iwai, K.
  • Organizer: Keystone Symposium "The Many Faces of Ubiquitin"(Invited)
  • Place of Presentation: Copper Mountain Resort, CO, USA
  • Year and Date: 20090111-20090116
• [Presentation] The COP9/Signalosome increases the efficiency of pVHL-containing ubiquitin ligase.mediated HIF-α ubiquitination. (2008)
  • Author(s): Miyauchi, Y., Kato, M., Tokunaga, F., Iwai, K.
  • Organizer: ZOMESV : The Fifth International Symposium on the COP9 signalosome, Proteasome and eIF3 : At the interface between signaling and proteolysis(Invited)
  • Place of Presentation: Yokohama, Japan.
  • Year and Date: 20081111-20081114
• [Presentation] Linear ubiquitination of NEMO triggers NF-kB activation. (2007)
  • Author(s): Tokunaga, F., Sakata, S.-I., Kirisako, T., Nakagawa, T., Murata, S.Tanaka, K.Iwai, K.
  • Organizer: The EMBO Conference "Ubiquitin and Ubiquitin-like Modifiers in Cellular Regulation"
  • Place of Presentation: Riva Del Garda, Italy.
  • Year and Date: 20070922-20070926
• [Presentation] Proteasomal ubiquitin receptor RPN-10 controls TRA-2-mediated sex determination in Caenorhabditis elegans. (Invited) (2006)
  • Author(s): Kawahara, H., Shimada, M., Yokosawa, H.
  • Organizer: 4th NIBB-EMBL Symposium
  • Place of Presentation: Okazaki, Japan,
  • Year and Date: 20061202-20061204
• [Presentation] Identification of a ligase complex polymerizing linear polyubiquitin chains and its physiological role. (2006)
  • Author(s): Kirisako, T., Tokunaga, F., Nakamura, M., Iwai, K.
  • Organizer: The Fourth NIBB-EMBL Symposium,(Invited)
  • Place of Presentation: Okazaki, Japan.
  • Year and Date: 20061202-20061204
• [Book] M.eds Landes Biosciences (2010)
  • Author(s): Iwai, K.
  • Publisher: FUNCTIONS OF LINEAR UBIQUITIN CHAINS IN THE NF-κB PATHWAY Linear Polyubiquitin in NF-κB Signaling. Conjugation and Deconjugation of Ubiquitin Family Modifiers Groettrup
• [Book] J, eds.John Wiley and Sons (2006)
  • Author(s): Lorick, K., Yang, Y., Jensen, J., Iwai, K.Weissman, A.M.
  • Total Pages: 1-12
  • Publisher: Studies of the ubiquitin proteasome system. Units 15.9 Current Protocols in Cell Biology Bonifacino J, Dasso M, Lippincott-Schwartz J, Harford J, Yamada K, Bonafacino
• [Remarks] ホームページ等
  • URL: http://www.cellbio.med.osaka-u.ac.jp/
• [Patent(Industrial Property Rights)] 新規なユビキチンリガーゼ及びその利用 (2010)
  • Inventor(s): 岩井一宏
  • Industrial Property Rights Holder: 大阪大学
  • Industrial Property Number: PCT,Jp2010/063345
  • Filing Date: 2010-08-06
• [Patent(Industrial Property Rights)] 新規なユビキチンリガーゼ及びその利用 (2009)
  • Inventor(s): 岩井一宏
  • Industrial Property Rights Holder: 大阪大学
  • Industrial Property Number: 特許,特願2009-184878
  • Filing Date: 2009-08-07