The study reveals that LUBAC acts downstream of the E3 ligase TRAF6 to fine-tune the activity of the CBM signaling complex, a key regulator of T cell activation. This modulation influences NF-κB target gene expression and MALT1 substrate recognition, identifying a new layer of control in the post-translational regulation of immune signaling.
“By uncovering how LUBAC and TRAF6 cooperate to regulate MALT1 protease activity, our study provides important clues for how this signaling pathway can be selectively targeted,” says Daniel Krappmann.
Understanding these regulatory mechanisms opens new avenues for therapeutic strategies aimed at modulating MALT1 protease activity – for example, to enhance anti-tumor immunity or to limit excessive inflammatory responses.
This work highlights a successful collaboration between the Molecular Targets and Therapeutics Center and the Computational Health Center at Helmholtz Munich, together with international and academic partners from the University of Melbourne (Australia), Friedrich Schiller University Jena, and Ludwig-Maximilians-University Munich. By combining molecular biology and computational modeling, the teams have advanced the understanding of signaling pathways that shape adaptive immunity.
Original publication
Graß et al., 2025: LUBAC modulates CBM complex functions downstream of TRAF6 in T cells. Nature Communications. DOI: 10.1038/s41467-025-65879-6
