Physiology and pathology of the ubiquitin-mediated quality control system

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 14GS0322
• Research Category: Grant-in-Aid for Creative Scientific Research
• Allocation Type: Single-year Grants
• Research Institution: Osaka City University
• Principal Investigator: IWAI Kazuhiro Osaka City University, Graduate School of Medicine, Professor (60252459)
• Co-Investigator(Kenkyū-buntansha): MORI Hiroshi Osaka City University, Graduate School of Medicine, Professor (10159189)
• Project Period (FY): 2002 – 2006
• Keywords: protein / biological molecules / stress / cancer / neurodegenerative diseases

Research Abstract

1. Functional analyses of the HOIL-1 ubiquitin ligase
a. Mechanism of target recognition by HOIL-1 A heme-regulatory motif (HRM) in IRP2 is the heme-binding site of IRP2. Oxidative modification of IRP2, generated by heme bound to the HRM and oxygen is recognized by HOIL-1, which leads to IRP2 ubiquitination. From these analyses, we show a novel iron-sensing mechanism, in which cells are sensing changes in iron concentration through heme (Nature Cell Biology, 2003; Molecular Cell, 2005).
b. Function of the ligase complex containing HOIL-1 The LUBAC ubiquitin ligase complex, composed of HOIP and HOIL-1L, an isoform of HOIL-1, generates a novel polyubiquitin chain, in which C-terminal Gly residue of ubiquitin is conjugated to a-amino group of N-terminal Met of ubiquitin (EMBO J. 2006).
c. Physiological roles of the HOIL-1 ligase We have shown that LUBAC selectively activates the NF-kB pathway through linear ubiquitination of NEMO (In submission).
2. We showed that the SCF^<Fbs1> ligase selectively recognizes the chitobiose portion of the N-linked sugar chain, which recognition mechanism is suitable for selective recognition of denatured glycoproteins (Nature, 2002; Nat. Strut. Mol. Biol., 2004).
3. We have generated transgenic mice expressing IRP2 in neuron (IRP2 Tg) and analyzed the roles of oxidative stress generated by perturbation of iron metabolism in neurodegenerative disorders. Although massive iron accumulation was not observed, reactive Fe 2+ was accumulated in IRP2 Tg neurons, which provokes oxidative damages in those cells. Also, neuronal loss and ataxia was observed in aged IRP2 Tg mice (In submission).

Research Products

• [Journal Article] A ubiquitin ligase complex assembles linear polyubiquitin chains (2006)
  • Author(s): Kirisako, T., Katnei, K., Murata, S., Kato, M., Fukumoto., H, , Kanie, K., Sano, S.Tokunaga, F., Tanaka, K.and Iwai, K.
  • Journal Title: EMBO J. 25・20 Pages: 4877-4887
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mutual regulation of conventional protein kinase C and a ubiquitin liease complex(LUBAC) (2006)
  • Author(s): Nakamura, M., Tokunaga, F., Sakata, S.-I.and Iwai, K.
  • Journal Title: Biochem.Biophys.Res.Commun. 351・2 Pages: 340-347
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Studies of the ubiquitin proteasome system (2006)
  • Author(s): Lorick, K., Yang, Y., Jensen, J., Iwai, K.and Weissman, A.M.
  • Journal Title: Units 15.9 Sections 1-12.Current Protocols in Cell Biology, Bonifacino J, Dasso M, Lippincott-Schwartz J, Harford J, Yamada K, eds.John Wiley and Sons Pages: 75
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mutual regulation of conventional protein kinase C and a ubiquitin ligase complex(LUBAC). (2006)
  • Author(s): Nakamura, M., Tokunaga, F., Sokoto, S.-I. and Iwai, K.
  • Journal Title: Biochem. Biophys. Res. Commun. 351 Pages: 340-347
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Studies of the ubiquitin proteasome system. Units 15.9 Sections 1-12. (2006)
  • Author(s): Lorick, K., Yang, Y., Jensen, J., Iwai, K., Weissman, A. M.
  • Journal Title: Current Protocols in Cell Biology Bonifacino J, Dasso M, Lippincott-Schwartz J, Harford J, Yamada K, eds. John Wiley and Sons 75
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2 (2005)
  • Author(s): Ishikawa, H., Kato, M., Hori, H., Ishmori, K., Kirisako, T., Tokunaga, F.and Iwai, K.
  • Journal Title: Molecular Cell 19 Pages: 171-181
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Invovlement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2. (2005)
  • Author(s): Ishikawa, H., Kato, M., Hori, H., Ishimori, K., Kirisako, T., Tokunaga, F., Iwai, K.
  • Journal Title: Molecular Cell. 19 Pages: 171-181
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Structural basis of sugar-recognizing ubiquitin ligase (2004)
  • Author(s): Mizushima, T., Hirao, T., Yoshida, Y., Lee, S.J., Chiba, T., Iwai, K., Yamaguchi, Y., Kato, K, Tsukihara, T.and Tallaka, K.
  • Journal Title: Nature Structural & Molecular Biology 11 Pages: 365-370
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Structural basis of sugar-recognizing ubiquitin ligase. (2004)
  • Author(s): Mizushima, T., Hiro, T., Yoshida, Y., Lee, S. J., Chiba, T., Iwai, K., Yamaguchi, Y., Kato, K., Tsukihara, T., Tanaka, K.
  • Journal Title: Nature Structural & Molecular Biology 11 Pages: 365 -370
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2 (2003)
  • Author(s): Yamanaka, K., Ishikawa, H., Megmni, Y., Tokunaga, F., Kanie, M., Rouault, T.A., Morishima L, Minato, N., Ishimori, K., Iwai, K.
  • Journal Title: Nature Cell Biology 5 Pages: 336-340
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2 (2003)
  • Author(s): Yamanaka, K., Ishikawa, H., Megumi, Y., Tokunaga, F., Kanie, M., Rouault, T. A., Morishima, I., Minato, N., Ishimori, K., Iwai K.
  • Journal Title: Nature Cell Biology 5 Pages: 336-340
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] E3 ubiquitin-ligase that recognises sugar chains (2002)
  • Author(s): Yosbida, Y., Chiba, T., Tokunaga, F., Kawasaki, H., Iwai K, Suzuki, T., Ito, Y., Matsuoka, K., Yoshida, M., Tanaka, K.and Tai, T.
  • Journal Title: Nature 418 Pages: 438-442
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] E3 ubiquitin-ligase that recognises sugar chains (2002)
  • Author(s): Yoshida, Y., Chiba, T., Tokunaga, F., Kawasaki, H., Iwai K., Suzuki, T., Ito, Y., Matsuoka, K., Yoshida, M., Tanaka, K., Tai, T.
  • Journal Title: Nature. 418 Pages: 438-442
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Studies of the ubiquitin proteasome system. Units 15.9 Sections 1-12. Current Protocols in Cell Biology (2006)
  • Author(s): Lorick, K., Yang, Y., Jensen, J., Iwai, K.and Weissman, A.M.
  • Total Pages: 75
  • Publisher: Bonifacino J, Dasso M, Lippincott-Schwartz J, Harford J, Yamada K, eds. John Wiley and Sons;
  • Description: 「研究成果報告書概要(和文)」より