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Fumiyo Ikeda

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Development and application of nanobody-based tools to monitor cellular dynamics of a target E3 ligase complex

Fumiyo Ikeda

Fumiyo Ikeda, DDS, PhD

Ubiquitin Biology Laboratory, Graduate School of Frontier Biosciences, Osaka University
Professor
https://www.fbs.osaka-u.ac.jp/en/research_group/detail/52

Research summary

Atypical ubiquitin (Ub) chains called linear Ub chains linked via Met-1 regulates inflammation, selective autophagy, and immunity. Linear Ub chains are generated by the only known Ub E3 ligase complex LUBAC and destroyed by the deubiquitinase OTULIN. These Ub chains are recognized specifically by at least seven proteins, of which event controls the downstream cellular signaling pathways. As such, proteins responsible for generation, destruction, and recognition of linear Ub chains have been determined, yet their dynamics in cells, specific signal network formation and biological roles in various tissues remain largely unclear. For example, human gene encoding HOIL-1L (a component of LUBAC) is related with autoimmune diseases, cancer and myopathy, however detailed mechanisms are not determined. Furthermore, there are no available specific/sensitive antibodies or molecular tools suitable these unknown functions, we aim to develop nanobody-based molecular tools. By using these new tools, we will elucidate more detailed regulatory mechanisms of LUBAC in various tissues (Aim 1), identity nanobody clones that regulate LUBAC activity (negatively or positively) and apply to cellular assays (Aim2), and develop GFP-nanobody suitable for tracing cellular dynamics of the LUBAC components (Aim 3) (Fig. 1). By pursuing these aims, ultimately, we expect to contribute developing a method to control diseases where LUBAC plays a role.

Publications

  1. Rodriguez Carvajal A, Grishkovskaya I, Gomez Diaz C, Vogel A, Sonn-Segev A, Kushwah MS, Schodl K, Deszcz L, Orban-Nemeth Z, Sakamoto S, Mechtler K, Kukura P, Clausen T, *Haselbach D, *Ikeda F.
    The linear ubiquitin chain assembly complex (LUBAC) generates heterotypic ubiquitin chains.
    eLife 10, e60660 (2021)
    PMID: 34142657
  2. Gomez Diaz C, Jonsson G, Schodl K, Deszcz L, Bestehorn A, Eislmayr K, Almagro J, Kavirayani A, Seida M, Fennell ML, Hagelkrueys A, Kovarik P,　Penninger MJ, *Ikeda F.
    The ubiquitin ligase HOIL-1L regulates immune responses by interacting with linear ubiquitin chains.
    iScience. 24, 103241 (2021)
    PMID: 34755089

Former Publications

  1. 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.
    SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis.
    Nature. 471, 637-641 (2011)
    PMID: 21455181
  2. Kumari S, Redouane Y, Lopez-Mosqueda J, Shiraishi R, Romanowska M, Lutzmayer S, Kuiper J, Martinez C, *Dikic I, *Pasparakis M, *Ikeda F.
    Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis.
    Elife. 3, e03422 (2014)
    PMID: 25443631
  3. *Rittinger K, *Ikeda F.
    Linear ubiquitin chains: enzymes, mechanisms and biology.
    Open Biol. 7, 170026 (2017)
    PMID: 28446710
  4. Ebner P, Poetsch I, Deszcz L, Hoffmann T, Zuber J, *Ikeda F.
    The IAP family member BRUCE regulates autophagosome-lysosome fusion.
    Nat Commun. 9, 599 (2018)
    PMID: 29426817
  5. Fennell LM, Gomez Diaz C, Deszcz L, Kavirayani A, Hoffmann D, Yanagitani K, Schleiffer A, Mechtler K, Hagelkruys A, Penninger J, *Ikeda F.
    Site-specific ubiquitination of the E3 ligase HOIP regulates apoptosis and immune signaling.
    EMBO J. 39, e103303 (2020)
    PMID: 33215740