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LUBAC modulates CBM complex functions downstream of TRAF6 in T cells

Author

Listed:
  • Carina Graß

    (Helmholtz Munich - German Research Center for Environmental Health)

  • Franziska Ober

    (Helmholtz Munich - German Research Center for Environmental Health)

  • Constanze Sixt

    (Helmholtz Munich - German Research Center for Environmental Health)

  • Bahareh Nemati Moud

    (Helmholtz Munich - German Research Center for Environmental Health)

  • Irina Antoshkina

    (Helmholtz Munich - German Research Center for Environmental Health)

  • Frederick Eberstadt

    (Helmholtz Munich - German Research Center for Environmental Health)

  • Alisa Puhach

    (Leibniz Institute for Natural Product Research and Infection Biology)

  • Göksu Avar

    (Helmholtz Munich
    The University of Melbourne)

  • Antonia Keßler

    (Helmholtz Munich - German Research Center for Environmental Health)

  • Thomas J. O’Neill

    (Helmholtz Munich - German Research Center for Environmental Health)

  • Thomas Seeholzer

    (Helmholtz Munich - German Research Center for Environmental Health)

  • Jan Kranich

    (Ludwig-Maximilians-Universität)

  • Thomas Brocker

    (Ludwig-Maximilians-Universität)

  • Katja Lammens

    (Ludwig-Maximilians-Universität)

  • Michael P. Menden

    (Helmholtz Munich
    The University of Melbourne)

  • Christina E. Zielinski

    (Leibniz Institute for Natural Product Research and Infection Biology
    Friedrich Schiller University)

  • Daniel Krappmann

    (Helmholtz Munich - German Research Center for Environmental Health
    Ludwig-Maximilians-Universität)

Abstract

The CARD11-BCL10-MALT1 (CBM) complex drives NF-κB signaling and MALT1 protease activation after T cell receptor (TCR) stimulation, forming a central signaling hub in adaptive immunity. Both linear ubiquitin chain assembly complex (LUBAC), consisting of HOIP, HOIL-1 and SHARPIN, and TRAF6 interact with the CBM complex. Still, the coordinated activity of these E3 ligases in controlling CBM activity remains elusive. Here we demonstrate that LUBAC, unlike TRAF6, is largely dispensable for TCR-induced NF-κB activation in human CD4+ T cells. However, HOIP contributes to NF-κB target gene expression and, with TRAF6, modulates MALT1 substrate recognition, influencing T cell responses. Further, LUBAC-mediated conjugation of Met1-linked ubiquitin chains to BCL10 strictly depends on TRAF6, but putative Met1-ubiquitin acceptor lysines in BCL10 serve essential structural roles that limit accessibility within BCL10-MALT1 filaments. Thus, LUBAC acts downstream of TRAF6 to modulate MALT1 substrate recognition and to catalyze BCL10 ubiquitination, which is incompatible with BCL10-MALT1 filament formation.

Suggested Citation

  • Carina Graß & Franziska Ober & Constanze Sixt & Bahareh Nemati Moud & Irina Antoshkina & Frederick Eberstadt & Alisa Puhach & Göksu Avar & Antonia Keßler & Thomas J. O’Neill & Thomas Seeholzer & Jan K, 2025. "LUBAC modulates CBM complex functions downstream of TRAF6 in T cells," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65879-6
    DOI: 10.1038/s41467-025-65879-6
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    1. Charis E. Teh & Najoua Lalaoui & Reema Jain & Antonia N. Policheni & Melanie Heinlein & Silvia Alvarez-Diaz & Julie M. Sheridan & Eva Rieser & Stefanie Deuser & Maurice Darding & Hui-Fern Koay & Yifan, 2016. "Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis," Nature Communications, Nature, vol. 7(1), pages 1-15, December.
    2. Leonard Campanello & Maria K Traver & Hari Shroff & Brian C Schaefer & Wolfgang Losert, 2021. "Signaling through polymerization and degradation: Analysis and simulations of T cell activation mediated by Bcl10," PLOS Computational Biology, Public Library of Science, vol. 17(5), pages 1-24, May.
    3. Theo Klein & Shan-Yu Fung & Florian Renner & Michael A. Blank & Antoine Dufour & Sohyeong Kang & Madison Bolger-Munro & Joshua M. Scurll & John J. Priatel & Patrick Schweigler & Samu Melkko & Michael , 2015. "The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling," Nature Communications, Nature, vol. 6(1), pages 1-17, December.
    4. Isabel Meininger & Richard A. Griesbach & Desheng Hu & Torben Gehring & Thomas Seeholzer & Arianna Bertossi & Jan Kranich & Andrea Oeckinghaus & Andrea C. Eitelhuber & Ute Greczmiel & Andreas Gewies &, 2016. "Alternative splicing of MALT1 controls signalling and activation of CD4+ T cells," Nature Communications, Nature, vol. 7(1), pages 1-15, September.
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