Kyushu University Academic Staff Educational and Research Activities Database
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Fumiyo Ikeda Last modified date:2021.07.16

Graduate School
生体防御医学研究所 医学系学府 炎症制御学分野

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 Reseacher Profiling Tool Kyushu University Pure
Academic Degree
Ph.D., D.D.S.
Country of degree conferring institution (Overseas)
Field of Specialization
inflammation, cell death, ubiquitin, autophagy
ORCID(Open Researcher and Contributor ID)
Total Priod of education and research career in the foreign country
Research Interests
  • Ubiquitin (Ub) is a small protein used for posttranslational modification of substrates. Ubiquitination regulates a multitude of biological functions and pathologies, such as inflammation, cancer, cell death, autophagy, proteasome-dependent protein degradation, cell cycle, and protein quality control. The diverse functional consequences of ubiquitination arise from the choice of substrate, the site of modification, the number of Ub molecules added, and the linkage type of conjugated Ub chains. For ubiquitination, E1 Ub activating enzymes, E2 Ub conjugating enzymes and E3 Ub ligases play a key role. In particular, E3 ligases are known to determine the substrate and the ubiquitination site. There are predicted to be more than 600 E3 ligases in humans, but their functions and molecular mechanisms are largely unknown.
    We made major contributions towards our understanding of the role of a novel linkage type of Ub chains, called linear Ub chains. Linear Ub chains are generated by an E3 Ub ligase complex, LUBAC (linear Ub chain assembly complex), and contribute to cell death and inflammatory signaling pathways as well as heat responses. However, there are many important points yet to be elucidated.
    In our new lab at Kyushu Univ, we continue aiming to understand how inflammation and proteostasis are regulated by the ubiquitin system. Given that Ub controls diverse biological functions beyond its role in stress responses, we expect that our results will have broad relevance to human development, health and diseases.
    keyword : inflammation, ubiquitin, cell death, autophagy, cellular signaling, proteostasis
Academic Activities
1. Alan Rodriguez Carvajal, Irina Grishkovskaya, Carlos Gomez Diaz, Antonia Vogel, Adar Sonn-Segev, Manish S Kushwah, Katrin Schodl, Luiza Deszcz, Zsuzsanna Orban-Nemeth, Shinji Sakamoto, Karl Mechtler, Philipp Kukura, Tim Clausen, David Haselbach, Fumiyo Ikeda, The linear ubiquitin chain assembly complex LUBAC generates heterotypic ubiquitin chains., eLife, 10.7554/eLife.60660, 10, 2021.06, The linear ubiquitin chain assembly complex (LUBAC) is the only known ubiquitin ligase for linear/Met1-linked ubiquitin chain formation. One of the LUBAC components, HOIL-1L, was recently shown to catalyse oxyester bond formation between ubiquitin and some substrates. However, oxyester bond formation in the context of LUBAC has not been directly observed. Here, we present the first 3D reconstruction of human LUBAC obtained by electron microscopy and report its generation of heterotypic ubiquitin chains containing linear linkages with oxyester-linked branches. We found that this event depends on HOIL-1L catalytic activity. By cross-linking mass spectrometry showing proximity between the catalytic RBR domains, a coordinated ubiquitin relay mechanism between the HOIP and HOIL-1L ligases is suggested. In mouse embryonic fibroblasts, these heterotypic chains were induced by TNF, which is reduced in cells expressing an HOIL-1L catalytic inactive mutant. In conclusion, we demonstrate that LUBAC assembles heterotypic ubiquitin chains by the concerted action of HOIP and HOIL-1L..
2. Lilian M Fennell, Carlos Gomez Diaz, Luiza Deszcz, Anoop Kavirayani, David Hoffmann, Kota Yanagitani, Alexander Schleiffer, Karl Mechtler, Astrid Hagelkruys, Josef Penninger, Fumiyo Ikeda, Site-specific ubiquitination of the E3 ligase HOIP regulates apoptosis and immune signaling., The EMBO journal, 10.15252/embj.2019103303, e103303, 2020.11, HOIP, the catalytic component of the linear ubiquitin chain assembly complex (LUBAC), is a critical regulator of inflammation. However, how HOIP itself is regulated to control inflammatory responses is unclear. Here, we discover that site-specific ubiquitination of K784 within human HOIP promotes tumor necrosis factor (TNF)-induced inflammatory signaling. A HOIP K784R mutant is catalytically active but shows reduced induction of an NF-κB reporter relative to wild-type HOIP. HOIP K784 is evolutionarily conserved, equivalent to HOIP K778 in mice. We generated HoipK778R/K778R knock-in mice, which show no overt developmental phenotypes; however, in response to TNF, HoipK778R/K778R mouse embryonic fibroblasts display mildly suppressed NF-κB activation and increased apoptotic markers. On the other hand, HOIP K778R enhances the TNF-induced formation of TNFR complex II and an interaction between TNFR complex II and LUBAC. Loss of the LUBAC component SHARPIN leads to embryonic lethality in HoipK778R/K778R mice, which is rescued by knockout of TNFR1. We propose that site-specific ubiquitination of HOIP regulates a LUBAC-dependent switch between survival and apoptosis in TNF signaling..
3. Tomoko Asaoka, Jorge Almagro, Christine Ehrhardt, Isabella Tsai, Alexander Schleiffer, Luiza Deszcz, Sini Junttila, Leonie Ringrose, Karl Mechtler, Anoop Kavirayani, Attila Gyenesei, Kay Hofmann, Peter Duchek, Katrin Rittinger, Fumiyo Ikeda, Linear ubiquitination by LUBEL has a role in Drosophila heat stress response, EMBO REPORTS, 10.15252/embr.201642378, 17, 11, 1624-1640, 2016.11, The HOIP ubiquitin E3 ligase generates linear ubiquitin chains by forming a complex with HOIL-1L and SHARPIN in mammals. Here, we provide the first evidence of linear ubiquitination induced by a HOIP orthologue in Drosophila. We identify Drosophila CG11321, which we named Linear Ubiquitin E3 ligase (LUBEL), and find that it catalyzes linear ubiquitination in vitro. We detect endogenous linear ubiquitin chain-derived peptides by mass spectrometry in Drosophila Schneider 2 cells and adult flies. Furthermore, using CRISPR/Cas9 technology, we establish linear ubiquitination-defective flies by mutating residues essential for the catalytic activity of LUBEL. Linear ubiquitination signals accumulate upon heat shock in flies. Interestingly, flies with LUBEL mutations display reduced survival and climbing defects upon heat shock, which is also observed upon specific LUBEL depletion in muscle. Thus, LUBEL is involved in the heat response by controlling linear ubiquitination in flies..
4. Snehlata Kumari, Younes Redouane, Jaime Lopez-Mosqueda, Ryoko Shiraishi, Malgorzata Romanowska, Stefan Lutzmayer, Jan Kuiper, Conception Martinez, Ivan Dikic, Manolis Pasparakis, Fumiyo Ikeda, Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis, ELIFE, 10.7554/eLife.03422, 3, 2014.12, Linear Ubiquitin chain Assembly Complex (LUBAC) is an E3 ligase complex that generates linear ubiquitin chains and is important for tumour necrosis factor (TNF) signaling activation. Mice lacking Sharpin, a critical subunit of LUBAC, spontaneously develop inflammatory lesions in the skin and other organs. Here we show that TNF receptor 1 (TNFR1)-associated death domain (TRADD)-dependent TNFR1 signaling in epidermal keratinocytes drives skin inflammation in Sharpin-deficient mice. Epidermis-restricted ablation of Fas-associated protein with death domain (FADD) combined with receptor-interacting protein kinase 3 (RIPK3) deficiency fully prevented skin inflammation, while single RIPK3 deficiency only delayed and partly ameliorated lesion development in Sharpin-deficient mice, showing that inflammation is primarily driven by TRADD- and FADD-dependent keratinocyte apoptosis while necroptosis plays a minor role. At the cellular level, Sharpin deficiency sensitized primary murine keratinocytes, human keratinocytes, and mouse embryonic fibroblasts to TNF-induced apoptosis. Depletion of FADD or TRADD in Sharpin-deficient HaCaT cells suppressed TNF-induced apoptosis, indicating the importance of FADD and TRADD in Sharpin-dependent anti-apoptosis signaling in keratinocytes..
5. Ikeda F, Deribe YL, Skånland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJ, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B, Dikic I, Nature, SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis., 10.1038/nature09814, 471, 7340, 637-U120, 2011.03, Ikeda F, Deribe YL, Skånland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJ, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B, Dikic I, Nature, 2011, vol. 471, no. 7340, pp. 637-641.
6. Fumiyo Ikeda, Nicola Crosetto, Ivan Dikic, What Determines the Specificity and Outcomes of Ubiquitin Signaling?, CELL, 10.1016/j.cell.2010.10.026, 143, 5, 677-681, 2010.11, Ubiquitin signals and ubiquitin-binding domains are implicated in almost every cellular process, but how is their functionality achieved in cells? We assess recent advances in monitoring the dynamics and specificity of ubiquitin networks in vivo and discuss challenges ahead..
7. Simin Rahighi, Fumiyo Ikeda, Masato Kawasaki, Masato Akutsu, Nobuhiro Suzuki, Ryuichi Kato, Tobias Kensche, Tamami Uejima, Stuart Bloor, David Komander, Felix Randow, Soichi Wakatsuki, Ivan Dikic, Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-kappa B Activation, CELL, 10.1016/j.cell.2009.03.007, 136, 6, 1098-1109, 2009.03, Activation of nuclear factor-kappa B (NF-kappa B), a key mediator of inducible transcription in immunity, requires binding of NF-kappa B essential modulator (NEMO) to ubiquitinated substrates. Here, we report that the UBAN (ubiquitin binding in ABIN and NEMO) motif of NEMO selectively binds linear (head-to-tail) ubiquitin chains. Crystal structures of the UBAN motif revealed a parallel coiled-coil dimer that formed a heterotetrameric complex with two linear diubiquitin molecules. The UBAN dimer contacted all four ubiquitin moieties, and the integrity of each binding site was required for efficient NF-kappa B activation. Binding occurred via a surface on the proximal ubiquitin moiety and the canonical Ile44 surface on the distal one, thereby providing specificity for linear chain recognition. Residues of NEMO involved in binding linear ubiquitin chains are required for NF-kappa B activation by TNF-alpha and other agonists, providing an explanation for the detrimental effect of NEMO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency..
8. Fumiyo Ikeda, Ivan Dikic, Atypical ubiquitin chains: new molecular signals - 'Protein modifications: Beyond the usual suspects' review series, EMBO REPORTS, 10.1038/embor.2008.93, 9, 6, 536-542, 2008.06, Ubiquitin (Ub) is a small protein modifier that regulates many biological processes, including gene transcription, cell-cycle progression, DNA repair, apoptosis, virus budding and receptor endocytosis. Ub can be conjugated to target proteins either as a monomer or as Ub chains that vary in length and linkage type. The various types of Ub modification are linked to distinct physiological functions in cells. MonoUb, for example, regulates DNA repair and receptor endocytosis, whereas lysine 48-linked Ub chains label proteins for proteasomal degradation. More recently, the importance of chains conjugated through the other six lysines in Ub, known as atypical Ub chains, has been revealed. Atypical chains can be homotypic, sequentially using the same lysine residue in Ub for conjugation; mixed-linkage, utilizing several distinct lysines to connect consecutive Ub moieties; or heterologous, connecting Ub with other Ub-like modifiers. Here, we describe recent progress in the understanding of atypical Ub chain assembly and their recognition by Ub-binding domains, and we discuss further their functional roles in vivo..
9. Fumiyo Ikeda, Christina Maria Hecker, Alexis Rozenknop, Rolf Dietrich Nordmeier, Vladimir Rogov, Kay Hofmann, Shizuo Akira, Volker Doetsch, Ivan Dikic, Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes, EMBO JOURNAL, 10.1038/sj.emboj.7601773, 26, 14, 3451-3462, 2007.07, TANK-binding kinase 1 (TBK1/NAK/T2K) and I-kappa B Kinase (IKK-i/IKK-epsilon) play important roles in the regulation of interferon (IFN)-inducible genes during the immune response to bacterial and viral infections. Cell stimulation with ssRNA virus, dsDNA virus or gram-negative bacteria leads to activation of TBK1 or IKK-i, which in turn phosphorylates the transcription factors, IFN-regulatory factor (IRF)3 and IRF7, promoting their translocation in the nucleus. To understand the molecular basis of activation of TBK1, we analyzed the sequence of TBK1 and IKK-i and identified a ubiquitin-like domain (ULD) adjacent to their kinase domains. Deletion or mutations of the ULD in TBK1 or IKK-i impaired activation of respective kinases, failed to induce IRF3 phosphorylation and nuclear localization and to activate IFN-beta or RANTES promoters. The importance of the ULD of TBK1 in LPS- or poly(I:C)-stimulated IFN-beta production was demonstrated by reconstitution experiments in TBK1-IKK-i-deficient cells. We propose that the ULD is a regulatory component of the TBK1/IKK-i kinases involved in the control of the kinase activation, substrate presentation and downstream signaling pathways..
10. Fumiyo Ikeda, Riko Nishimura, Takuma Matsubara, Kenji Hata, Sakamuri V. Reddy, Toshiyuki Yoneda, Activation of NFAT signal in vivo leads to osteopenia associated with increased osteoclastogenesis and bone-resorbing activity, JOURNAL OF IMMUNOLOGY, 10.4049/jimmunol.177.4.2384, 177, 4, 2384-2390, 2006.08, The transcription factor family member NFAT plays an important role in the regulation of osteoclast differentiation. However, the role of NFAT in osteoclasts in vivo is still not fully understood. Thus, we generated transgenic mice in which constitutively active-NFAT1/NFATc2 (CA-NFAT1) is specifically expressed in the osteoclast lineage, using the tartrate-resistant acid phosphatase gene promoter. Both x-ray and histological analyses demonstrated an osteopenic bone phenotype in the CA-NFAT1 transgenic mice, whereas the number of tartrate-resistant acid phosphatase-positive osteoclasts was markedly higher in the long bones of these mice. Furthermore, the bone-resorbing activity of mature osteoclasts derived from the transgenic mice was much higher than that of wild-type mice. Interestingly, the introduction of CA-NFAT1 into osteoclasts or RAW264 cells increased the expression and activity of c-Src and stimulated actin ring formation. In contrast, CA-NFAT1 or GFP-tagged VIVIT peptide, a specific inhibitor of NFAT, did not affect the survival of mature osteoclasts. Collectively, our data indicate that NFAT controls bone resorption in vivo by stimulating the differentiation and functioning of osteoclasts but not their survival..
11. F Ikeda, R Nishimura, T Matsubara, S Tanaka, J Inoue, SV Reddy, K Hata, K Yamashita, T Hiraga, T Watanabe, T Kukita, K Yoshioka, A Rao, T Yoneda, Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation, JOURNAL OF CLINICAL INVESTIGATION, 10.1172/JCI200419657, 114, 4, 475-484, 2004.08, Receptor activator of NF-kappaB ligand (RANKL) plays an essential role in osteoclast formation and bone resorption. Although genetic and biochemical studies indicate that RANKL regulates osteoclast differentiation by activating receptor activator of NF-kappaB and associated signaling molecules, the molecular mechanisms of RANKL-regulated osteoclast differentiation have not yet been fully established. We investigated the role of the transcription factor c-Jun, which is activated by RANKL, in osteoclastogenesis using transgenic mice expressing dominant-negative c-Jun specifically in the osteoclast lineage. We found that the transgenic mice manifested severe osteopetrosis due to impaired osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited soluble RANKL-induced osteoclast differentiation in vitro. Overexpression of nuclear factor of activated T cells 1 (NFAT1) (NFATc2/NFATp) or NFAT2 (NFATc1/NFATc) promoted differentiation of osteoclast precursor cells into tartrate-resistant acid phosphatase-positive (TRAP-positive) multinucleated osteoclast-like cells even in the absence of RANKL. Overexpression of NFAT1 also markedly transactivated the TRAP gene promoter. These osteoclastogenic activities of NFAT were abrogated by overexpression of dominant-negative c-Jun. Importantly, osteoclast differentiation and induction of NFAT2 expression by NFAT1 overexpression or soluble RANKL treatment were profoundly diminished in spleen cells of the transgenic mice. Collectively, these results indicate that c-Jun signaling in cooperation with NFAT is crucial for RANKL-regulated osteoclast differentiation..
Membership in Academic Society
  • The American Society for Cell Biology
Other Educational Activities
  • 2011.11.