Screening for interactors of linear ubiquitin chain assembly complex (LUBAC), and studies on their physiological functions
| Project/Area Number |
15H04694
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Osaka City University (2016-2017)
Gunma University (2015) |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
SAWASAKI Tatsuya 愛媛大学, プロテオサイエンスセンター, 教授 (50314969)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2016: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
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| Keywords | 酵素 / タンパク質 / 細胞・ 組織 / シグナル伝達 / 炎症 / 蛋白質 / 細胞・組織 / 免疫学 / 生理活性 |
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| Outline of Final Research Achievements |
We identified LUBAC ubiquitin ligase complex, which specifically generates the N-terminal Met(M)1-linked linear polyubiquitin chain, and LUBAC is involved in the NF-κB activation pathway to regulate innate immune and inflammatory responses. In this study, we focused on optineurin (OPTN), a linear ubiquitin-binding and NF-κB-suppressive protein. Wild-type OPTN down-regulates NF-κB activation and apoptosis, whereas OPTN mutants which cause amyotrophic lateral sclerosis (ALS) failed to suppress these cellular functions due to the lack of linear ubiquitin binding ability. Furthermore, immunohistochemical analyses of motor neurons from OPTN-associated ALS patients revealed that linear ubiquitin and activated NF-κB partially colocalized with cytoplasmic inclusions. Taken together, OPTN regulates both NF-κB activation and apoptosis via linear ubiquitin-binding, and the loss of this ability may lead to ALS by sustained neuroinflammation and enhanced apoptosis.
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Report
(4 results)
Research Products
(48 results)
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[Journal Article] In-frame VIn-frame Val216-Ser217 deletion of KIT in mild piebaldism causes aberrant secretion and SCF response.2018
Author(s)
Hattori M, Ishikawa O, Oikawa D, Amano H, Yasuda M, Kaira K, Ishida-Yamamoto A, Nakano H, Sawamura D, Terawaki S, Wakamatsu K, Tokunaga F, Shimizu A
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Journal Title
J. Dermatol. Sci.
Volume: -
Related Report
Peer Reviewed
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[Journal Article] Mechanistic insight into the repigmentation of piebaldism: functional characterization of a mutant KIT in melanocyte regeneration.2018
Author(s)
Hattori M, Oikawa D, Amano H, Yasuda M, Kaira K, Ishida-Yamamoto A, Nakano H, Sawamura D, Terawaki S, Wakamatsu K, Tokunaga F, Ishikawa O, Shimizu A.
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Journal Title
Related Report
Peer Reviewed
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[Journal Article] HTLV-1 Tax induces formation of the active macromolecular IKK complex by generating Lys63- and Met1-linked hybrid polyubiquitin chains.2017
Author(s)
Shibata Y, Tokunaga F, Goto E, Komatsu G, Gohda J, Saeki Y, Tanaka K, Takahashi H, Sawasaki T, Inoue S, Oshiumi H, Seya T, Nakano H, Tanaka Y, Iwai K, and Inoue J.
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Journal Title
PLoS Pathog.
Volume: 13
Issue: 12
Pages: e1006162-e1006162
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Reduced SHARPIN and LUBAC formation may contribute to CCl4- or acetaminophen-induced liver cirrhosis in mice.2017
Author(s)
Yamamotoya T, Nakatsu Y, Matsunaga Y, Fukushima T, Yamazaki H, Kaneko S, Fujishiro M, Kikuchi T, Kushiyama A, Tokunaga F, Asano T, and Sakoda H.
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Journal Title
Int. J. Mol. Sci.
Volume: 18
Issue: 2
Pages: 326-326
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis.2016
Author(s)
Nakazawa S, Oikawa D, Ishii R, Ayaki T, Takahashi H, Takeda H, Ishitani R, Kamei K, Takeyoshi I, Kawakami H, Iwai K, Hatada I, Sawasaki T, Ito H, Nureki O, and Tokunaga F.
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Journal Title
Nat. Commun.
Volume: 7
Issue: 1
Pages: 12547-12547
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[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.
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Journal Title
Mediators Inflamm.
Volume: 2015
Issue: 1
Pages: 125380-125380
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
PLoS One.
Volume: 10
Issue: 10
Pages: e0140366-e0140366
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A20 targets caspase-8 and FADD to protect HTLV-I-infected cells.2015
Author(s)
Saitoh Y, Hamano A, Mochida K, Kakeya A, Uno M, Tsuruyama E, Ichikawa H, Tokunaga F, Utsunomiya A, Watanabe T, Yamaoka S
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Journal Title
Leukemia
Volume: 30
Issue: 3
Pages: 716-726
DOI
Related Report
Peer Reviewed
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