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Mathematical Simulation of Linear Ubiquitination in T Cell Receptor-Mediated NF-κB Activation Pathway

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Methods of Mathematical Oncology (MMDS 2020)

Part of the book series: Springer Proceedings in Mathematics & Statistics ((PROMS,volume 370))

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Abstract

The linear ubiquitin chain assembly complex (LUBAC), composed of the HOIP, HOIL-1L, and SHARPIN subunits, activates the canonical nuclear factor-κB (NF-κB) pathway through the Met1 (M1)-linked linear ubiquitination activity. On the course of the T cell receptor (TCR)-mediated NF-κB activation pathway, LUBAC transiently associates with and linearly ubiquitinates the CARMA1-BCL10-MALT1 (CBM) complex. In contrast, the linear ubiquitination of NEMO, a substrate of the TNF-α-induced NF-κB activation pathway, was limited in the TCR pathway. A linear ubiquitin-specific deubiquitinase (DUB), OTULIN, plays a major role in downregulating LUBAC-mediated TCR signaling. Mathematical modeling indicated that linear ubiquitination of the CBM complex accelerates the activation of IκB kinase (IKK), as compared with the activity induced by linear ubiquitination of NEMO alone. Moreover, simulations of the sequential linear ubiquitination of the CBM complex suggested that the allosteric regulation of linear (de)ubiquitination of CBM subunits is controlled by the ubiquitin-linkage lengths. Thus, unlike the TNF-α-induced NF-κB activation pathway, the TCR-mediated NF-κB activation in T cells has a characteristic mechanism to induce LUBAC-mediated NF-κB activation.

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Authors and Affiliations

  1. Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan

    Daisuke Oikawa & Fuminori Tokunaga

  2. Division of Mathematical Science, Department of Systems Innovation, Graduate School of Engineering Science, Osaka University, Toyonaka, Japan

    Naoya Hatanaka

  3. Center for Mathematical Modeling and Data Science, Osaka University, Toyonaka, Japan

    Takashi Suzuki

Authors
  1. Daisuke Oikawa
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  2. Naoya Hatanaka
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  3. Takashi Suzuki
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  4. Fuminori Tokunaga
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Corresponding author

Correspondence to Fuminori Tokunaga .

Editor information

Editors and Affiliations

  1. Centre for Mathematical Modeling and Data Science, Osaka University, Toyonaka, Japan

    Takashi Suzuki

  2. Research Team MONC, Institut de Mathématiques de Bordeaux (CNRS UMR 5251), Talence, France

    Clair Poignard

  3. School of Mathematics and Statistics, MI, University of St Andrews, St Andrews, UK

    Mark Chaplain

  4. Quantitative Systems Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    Vito Quaranta

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Oikawa, D., Hatanaka, N., Suzuki, T., Tokunaga, F. (2021). Mathematical Simulation of Linear Ubiquitination in T Cell Receptor-Mediated NF-κB Activation Pathway. In: Suzuki, T., Poignard, C., Chaplain, M., Quaranta, V. (eds) Methods of Mathematical Oncology. MMDS 2020. Springer Proceedings in Mathematics & Statistics, vol 370. Springer, Singapore. https://doi.org/10.1007/978-981-16-4866-3_14

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