# LUBAC modulates CBM complex functions downstream of TRAF6 in T cells

## TL;DR

This study explores how LUBAC and TRAF6 regulate the CBM complex in T cells, revealing that LUBAC modifies BCL10 and influences MALT1 activity.

## Contribution

The study identifies LUBAC's role in modulating MALT1 substrate recognition and BCL10 ubiquitination downstream of TRAF6 in T cells.

## Key findings

- LUBAC is largely dispensable for TCR-induced NF-κB activation in human CD4+ T cells.
- HOIP contributes to NF-κB target gene expression and modulates MALT1 substrate recognition with TRAF6.
- LUBAC-mediated ubiquitination of BCL10 depends on TRAF6 and affects BCL10-MALT1 filament formation.

## 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.

The CARD11-BCL10-MALT1 (CBM) complex governs canonical NF-κB signaling and MALT1 protease activation downstream of TCR stimulation. Here, the authors evaluate the contribution of the E3 ligases LUBAC and TRAF6 in controlling CBM activity, using Jurkat and primary human T cells. Unlike TRAF6, LUBAC is largely dispensable for activating NF-κB, but it modifies BCL10 and regulates MALT1 protease activity by controlling substrate selectivity.