LUBAC modulates CBM complex functions downstream of TRAF6 in T cells

Area of Science:

• Immunology
• Molecular Biology
• Cell Signaling

Background:

• The CARD11-BCL10-MALT1 (CBM) complex is crucial for T cell receptor (TCR) signaling and NF-κB activation.
• Both the linear ubiquitin chain assembly complex (LUBAC) and TRAF6 interact with the CBM complex, but their coordinated roles are unclear.

Purpose of the Study:

• To elucidate the distinct and coordinated roles of LUBAC and TRAF6 in regulating CBM complex activity following TCR stimulation.
• To investigate how these E3 ligases influence NF-κB signaling, MALT1 protease activity, and downstream T cell responses.

Main Methods:

• Utilized human CD4+ T cells to assess TCR-induced NF-κB activation.
• Investigated the impact of LUBAC and TRAF6 on NF-κB target gene expression.
• Analyzed MALT1 substrate recognition and BCL10 ubiquitination in response to LUBAC and TRAF6 activity.
• Examined the structural consequences of BCL10 ubiquitination on CBM complex filament formation.

Main Results:

• LUBAC is largely dispensable for TCR-induced NF-κB activation in human CD4+ T cells, unlike TRAF6.
• HOIP, a component of LUBAC, contributes to NF-κB target gene expression.
• LUBAC and TRAF6 collaboratively modulate MALT1 substrate recognition, affecting T cell responses.
• LUBAC-mediated Met1-linked ubiquitination of BCL10 is TRAF6-dependent.
• Ubiquitination sites on BCL10 are structurally important, limiting filament formation and suggesting LUBAC acts downstream of TRAF6.

Conclusions:

• LUBAC plays a regulatory role downstream of TRAF6 in TCR signaling, modulating MALT1 activity and BCL10 ubiquitination.
• LUBAC-catalyzed BCL10 ubiquitination inhibits CBM complex filament formation, providing a mechanism to control signaling duration and intensity.
• These findings clarify the distinct contributions of LUBAC and TRAF6 to adaptive immunity signaling pathways.