LUBAC modulates CBM complex functions downstream of TRAF6 in T cells
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<sup>+</sup> 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.
Authors
- Franziska Ober
- Irina V. Antoshkina (ORCID: https://orcid.org/0000-0003-2403-8508)
- Bahareh Nemati Moud (ORCID: https://orcid.org/0000-0002-8529-1171)
- Thomas Brocker (ORCID: https://orcid.org/0000-0001-7060-5433)
- Daniel Krappmann (ORCID: https://orcid.org/0000-0001-7640-3234)
- Carina Graß
- Katja Lammens (ORCID: https://orcid.org/0000-0002-4438-1381)
- Thomas J. O’Neill (ORCID: https://orcid.org/0000-0003-2253-3118)
- Michael P. Menden (ORCID: https://orcid.org/0000-0003-0267-5792)
- Jan Kranich (ORCID: https://orcid.org/0000-0002-9928-4132)
- Christina E. Zielinski (ORCID: https://orcid.org/0000-0002-8184-0858)
- Alisa Puhach (ORCID: https://orcid.org/0000-0002-5090-8223)
- Thomas Seeholzer (ORCID: https://orcid.org/0000-0002-1115-3358)
- Göksu Avar (ORCID: https://orcid.org/0000-0002-2387-1154)
- Anne Kessler
- Constanze Sixt (ORCID: https://orcid.org/0009-0000-0953-9633)
- Frederick Eberstadt
Institutions
- The University of Melbourne (AU)
- Helmholtz Zentrum München (DE)
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
- Friedrich Schiller University Jena (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-10
- DOI
- https://doi.org/10.1038/s41467-025-65879-6
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- Leibniz-Gemeinschaft
- Helmholtz Zentrum München