LUBAC modulates CBM complex functions downstream of TRAF6 in T cells

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 Kranich, Thomas Brocker, Katja Lammens, Michael P. Menden, Christina E. Zielinski and Daniel Krappmann ()
Additional contact information
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
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
Christina E. Zielinski: Leibniz Institute for Natural Product Research and Infection Biology
Daniel Krappmann: Helmholtz Munich - German Research Center for Environmental Health

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65879-6

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