Patho-physiological function of the ubiquitin ligase that generates linear ubiquitin chains (LUBAC)

• Project/Area Number: 25253019
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: IWAI Kazuhiro 京都大学, 医学研究科, 教授 (60252459)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥46,670,000 (Direct Cost: ¥35,900,000、Indirect Cost: ¥10,770,000); Fiscal Year 2015: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000); Fiscal Year 2014: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000); Fiscal Year 2013: ¥21,710,000 (Direct Cost: ¥16,700,000、Indirect Cost: ¥5,010,000)
• Keywords: ユビキチン / 慢性炎症 / NF-kappaB / 細胞死 / 生体分子医学

Outline of Final Research Achievements

Linear ubiquitin chains and the LUBAC ubiquitin ligase that specifically generate linear chains are involved in NF-kappaB activation and cell death suppression. LUBAC is composed of catalytic HOIP and accessory SHARPIN and HOIL-1L subunits. In this research project, we analyzed functional difference between SHARPIN and HOIL-1L. Although both subunits have NZF domains that can bind to ubiquitin, SHARPIN NZF but not that of HOIL-1L can bind to K63-linked chains. Since LUBAC can be recruited to the activated receptor complex by recognizing K63 chains, loss of SHARPIN attenuated the recruitment of LUBAC to the receptor complex. Then loss of SHARPIN augmented cell death, which leads to the chronic dermatitis that specifically observed in SHARPIN null mice.

Research Products

• [Journal Article] Differential involvement of the NZF domains of SHARPIN and HOIL-1L in LUBAC-mediated cell death protection. (2016)
  • Author(s): Shimizu S, Fujita H, Sasaki Y, Tsuruyama T, Fukuda K, Iwai K.
  • Journal Title: Mol Cell Biol. Volume: 01049-15 Issue: 10 Pages: 1569-1583
  • DOI: 10.1128/mcb.01049-15
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis. (2015)
  • Author(s): Matsunaga Y, Nakatsu Y, Fukushima T, Okubo H, Iwashita M, Sakoda H, Fujishiro M, Yamamotoya T, Kushiyama A, Takahashi S, Tsuchiya Y, Kamata H, Tokunaga F, Iwai K, Asano T.
  • Journal Title: Mediators Inflamm. Volume: 2015 Issue: 1 Pages: 125380-125380
  • DOI: 10.1155/2015/125380
  • Peer Reviewed / Open Access
• [Journal Article] CYLD and the NEMO zinc finger regulate tumor necrosis factor signaling and early embryogenesis. (2015)
  • Author(s): Zhao, Y., Ma, C. A., Wu, L., Iwai, K., Ashwell, J. D., Oltz, E. M., Ballard, D. W., and Jain, A.
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 36 Pages: 22076-22084
  • DOI: 10.1074/jbc.m115.658096
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The Structural Differences between a Glycoprotein Specific F-Box Protein Fbs1 and Its Homologous Protein FBG3. (2015)
  • Author(s): Kumanomidou T, Nishio K, Takagi K, Nakagawa T, Suzuki A, Yamane T, Tokunaga F, Iwai K, Murakami A, Yoshida Y, Tanaka K, Mizushima T.
  • Journal Title: PLoS One. Volume: 10 Issue: 10 Pages: e0140366-e0140366
  • DOI: 10.1371/journal.pone.0140366
  • Peer Reviewed / Open Access
• [Journal Article] Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation. (2015)
  • Author(s): Bowman, J., Rodgers, M.A., Shi, M., Amatya, R., Hostager, B., Iwai, K., Gao, S.J., and Jung, J.U.
  • Journal Title: MBio. Volume: 6 Issue: 6
  • DOI: 10.1128/mbio.01777-15
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Roles of linear ubiquitinylation, a crucial regulator of NF-κB and cell death, in the immune system. (2015)
  • Author(s): Sasaki, K. and Iwai, K.
  • Journal Title: Immunol. Rev. Volume: 266 Issue: 1 Pages: 175-189
  • DOI: 10.1111/imr.12308
  • NAID: 120005672572
  • Peer Reviewed
• [Journal Article] Gliotoxin Suppresses NF-kappaB Activation by Selectively Inhibiting Linear Ubiquitin Chain Assembly Complex (LUBAC) (2015)
  • Author(s): Hiroki Sakamoto, Shinichiro Egashira, Nae Saito, Takayoshi Kirisako, Simon Miller, Yoshiteru Sasaki, Tadahiko Matsumoto, Manabu Shimonishi, Toru Komatsu, Takuya Terai, Tasuku Ueno, Kenjiro Hanaoka, Hirotatsu Kojima, Takayoshi Okabe, Soichi Wakatsuki, Kazuhiro Iwai, Tetsuo Nagano
  • Journal Title: ACS Chemical Biology Volume: 10 Issue: 3 Pages: 675-681
  • DOI: 10.1021/cb500653y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The unexpected role of polyubiquitin chains in the formation of fibrillar aggregates. (2015)
  • Author(s): Morimoto D,Walinda E, Fukada H, Sou YS, Kageyama S, Hoshino M, Fujii T, Tsuchiya H, Saeki Y, Arita K, Ariyoshi M, Tochio H, Iwai K, Namba K, Komatsu M, Tanaka K, Shirakawa M.
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 6116-6116
  • DOI: 10.1038/ncomms7116
  • NAID: 120005528125
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection. (2015)
  • Author(s): MacDuff, D. A., Reese, T. A,, Kimmey, J. M., Weiss, L. A., Song, C., Zhang, X., Kambal, A., Duan, E., Carrero, J. A., Boisson, B., Laplantine, E., Israel, A., Picard, C., Colonna, M., Edelson, B. T., Sibley, L. D., Stallings, C. L., Casanova, J. L., Iwai, K., Virgin, H. W.
  • Journal Title: eLife Volume: 4
  • DOI: 10.7554/elife.04494
  • NAID: 120005997705
  • Peer Reviewed
• [Journal Article] IFN-γ or IFN-α ameliorates chronic proliferative dermatitis by inducing expression of linear ubiquitin chain assembly complex. (2014)
  • Author(s): Tamiya H, Terao M, Takiuchi T, Nakahara M, Sasaki Y, Katayama I, Yoshikawa H, and Iwai K.
  • Journal Title: J. Immunol. Volume: 192 Issue: 8 Pages: 3793-3804
  • DOI: 10.4049/jimmunol.1302308
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. (2014)
  • Author(s): Rodgers, M. A., Bowman, J., Fujita, H., Orazio, N., Shi, M., Liang, Q., Amatya, R., Kelly, T. J., Iwai, K., Ting, J., and Jung, J. U.
  • Journal Title: J. Exp. Med. Volume: 211 Issue: 7 Pages: 1333-1347
  • DOI: 10.1084/jem.20132486
  • Peer Reviewed
• [Journal Article] HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth. (2014)
  • Author(s): Queisser, M. A., Dada, L. A., Deiss-Yehiely, N., Angulo, M., Zhou, G., Kouri, F. M., Knab, L. M., Liu, J., Stegh, A. H., DeCamp, M. M., Budinger, G. R., Chandel, N. S., Ciechanover, A., Iwai, K., and Sznajder, J. I.
  • Journal Title: Am. J. Respir. Crit. Care Med. Volume: 190 Issue: 6 Pages: 688-698
  • DOI: 10.1164/rccm.201403-0463oc
  • Peer Reviewed
• [Journal Article] Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN. (2014)
  • Author(s): Takiuchi, T., Nakagawa, T., Tamiya, H., Fujita, H., Sasaki, Y., Saeki, Y., Takeda, H., Sawasaki, T., Buchberger, A., Kimura, T., and Iwai. K.
  • Journal Title: Genes Cells. Volume: 19 Issue: 3 Pages: 254-272
  • DOI: 10.1111/gtc.12128
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mechanism underlying IKK activation mediated by the linear ubiquitin chain assembly complex (LUBAC). (2014)
  • Author(s): Fujita, H., Rahighi, S., Akita, M., Kato, R., Sasaki, Y., Wakatsuki, S., and Iwai, K.
  • Journal Title: Mol. Cell. Biol. Volume: 34 Issue: 7 Pages: 1322-1335
  • DOI: 10.1128/mcb.01538-13
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. (2014)
  • Author(s): Yang, Y., Schmitz, R., et al.
  • Journal Title: Cancer Discov. Volume: 4 Issue: 4 Pages: 480-493
  • DOI: 10.1158/2159-8290.cd-13-0915
  • Peer Reviewed
• [Journal Article] Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells (2013)
  • Author(s): Sasaki, Y., Sano, S., Nakahara, M., Murata, S., Kometani, K., Aiba, Y., Sakamoto, S., Watanabe, Y., Tanaka, K., Kurosaki, T., and lwai, K.
  • Journal Title: EMBO J. Volume: 32 Issue: 18 Pages: 2463-2476
  • DOI: 10.1038/emboj.2013.184
  • Peer Reviewed
• [Journal Article] Recruitment of the autophagic machinery to endosomes during infection is mediated by ubiquitin (2013)
  • Author(s): Naonobu Fujita et al.
  • Journal Title: J. Cell Biol. Volume: 203 Issue: 1 Pages: 115-128
  • DOI: 10.1083/jcb.201304188
  • Peer Reviewed / Open Access
• [Journal Article] Two coordinated mechanisms underlie TNFα-induced immediate and delayed IKK activation. (2013)
  • Author(s): Blackwell, K., Zhang, L., Workman, L.M., Ting, A.T., Iwai, K., Habelhah, H.
  • Journal Title: Mol. Cell. Biol. Volume: 33 Issue: 10 Pages: 1901-1915
  • DOI: 10.1128/mcb.01416-12
  • Peer Reviewed
• [Journal Article] IOP1 protein is an external component of the human cytosolic iron-sulfur cluster assembly (CIA) machinery and functions in the MMS19 protein-dependent CIA pathway (2013)
  • Author(s): Mineaki Seki, Yukiko Takeda, Kazuhiro Iwai and Kiyoji Tanaka
  • Journal Title: Journal of Biological Chemistry Volume: 288 Issue: 23 Pages: 16680-16689
  • DOI: 10.1074/jbc.m112.416602
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Differential involvement of subunits of LUBAC ubiquitin ligase in signalling and cell death. (2015)
  • Author(s): Shimizu, S., Fujita, H., Sasaki, Y., and Iwai, K.
  • Organizer: EMBO Conference “Ubiquitin and ubiquitin-like modifiers: From molecular mechanisms to human diseases”
  • Place of Presentation: Cavtat, Croatia
  • Year and Date: 2015-09-18
  • Int'l Joint Research / Invited
• [Presentation] Linear ubiquitin chains: NF-kappaB activation, cell death, and cancer. (2015)
  • Author(s): Iwai, K.
  • Organizer: International Symposium on Ubiquitin and Diseases.
  • Place of Presentation: Zhangjiajie, China
  • Year and Date: 2015-06-14
  • Int'l Joint Research / Invited
• [Presentation] LUBAC-mediated linear ubiquitination by a virulence factor of Aspergillus, gliotoxin. (2015)
  • Author(s): Sakamoto, H., Egashira, S., Okabe, T., Nagano, T., and Iwai, K.
  • Organizer: Cold Spring Harbor Laboratory meeting “The Ubiquitin Family”
  • Place of Presentation: Cold Spring Harbor, NY, USA
  • Year and Date: 2015-04-21
  • Int'l Joint Research
• [Presentation] Linear ubiquitin chains: a new regulator of NF-kappaB activation and cell death signaling. (2015)
  • Author(s): Iwai, K.
  • Organizer: 1st SPS International Symposium Xiamen University
  • Place of Presentation: Xiamen, China
  • Int'l Joint Research / Invited
• [Presentation] Phenotypical difference between mice lacking subunits of LUBAC ubiquitin ligase. (2014)
  • Author(s): Iwai, K.
  • Organizer: 1st International Symposium for New Aspects of the Ubiquitin Research
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2014-11-10
  • Invited
• [Presentation] Induction of expression of linear ubiquitin chain generating LUBAC ligase and amelioration of dermatitis in cpdm mice by interferons. (2014)
  • Author(s): Tamiya, H. and Iwai, K.
  • Organizer: he EMBO conference “Ubiquitin & ubiquitin-like proteins: At the crossroads from chromatin to protein”
  • Place of Presentation: Buenos Aires, Argentina
  • Year and Date: 2014-10-19
  • Int'l Joint Research
• [Presentation] Mechanism underlying linear ubiquitin-mediated NF-κB activation. (2014)
  • Author(s): Iwai, K.
  • Organizer: Benzon Symposium Nuclear regulation by ubiquitin
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2014-08-18
  • Int'l Joint Research
• [Presentation] Linear ubiquitination : a new regulator of NF-κB and cell death signaling. (2014)
  • Author(s): Iwai, K.
  • Organizer: 2014 International Conference on Protein Metabolism & Diseases
  • Place of Presentation: Yangyang, Korea
  • Year and Date: 2014-07-09
  • Int'l Joint Research / Invited
• [Presentation] Molecular mechanism and regulation of linear chain-mediated NF-κB activation. (2014)
  • Author(s): Fujita, H., Takiuchi, T., and Iwai, K.
  • Organizer: Cold Spring Harbor Asia Conference “ Protein Modifications & Homeostasis”
  • Place of Presentation: Suzhou, China
  • Year and Date: 2014-06-16
  • Int'l Joint Research / Invited
• [Presentation] Linear Polyubiquitination: a Crucial Regulator of NF-κB Activation. (2014)
  • Author(s): Iwai, K.
  • Organizer: THE UEHARA MEMORIAL FOUNDATION SYMPOSIUM 2014, Innovative Medicine : Basic Research and Development.
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2014-06-14
  • Int'l Joint Research / Invited
• [Presentation] Differential requirement of LUBAC-mediated linear polyubiquitination in CD40- or BCR-mediated canonical NF-κB activation in B cells (2013)
  • Author(s): Sasaki, Y., Fujita, H., and Iwai, K.
  • Organizer: The EMBO Conference “Ubiquitin and Ubiquitin-like Proteins: From structure to function”
  • Place of Presentation: Riva del Garda, Italy
  • Year and Date: 2013-10-01 – 2013-10-05
• [Presentation] Linear polyubiquitination: a new regulator of NF-κB activation. (2013)
  • Author(s): Iwai, K.
  • Organizer: The 35th Naito Conference “The Ubiquitin-Proteasome System: From Basic Mechanisms to Pathophysiological Roles”
  • Place of Presentation: Sapporo, Japan
  • Year and Date: 2013-07-09 – 2013-07-12
  • Invited
• [Presentation] Linear polyubiquitination: a new regulator of NF-κB activation. (2013)
  • Author(s): Iwai, K.
  • Organizer: The 38th FEBS congress symposium “Regulation of biological processes by ubiquitin and ubiquitin-like proteins in health and disease: proteolysis, autophagy and apoptosis”
  • Place of Presentation: St. Petersburg, Russia
  • Year and Date: 2013-07-06 – 2013-07-12
  • Invited
• [Remarks] 京都大学・大学院医学研究科・細胞機能制御学
  • URL: http://mcp.med.kyoto-u.ac.jp/
• [Remarks] 京都大学・大学院医学研究科・細胞機能制御学
  • URL: http://www.mcp.med.kyoto-u.ac.jp/