Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation.

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• The paracaspase Malt1 is a key regulator of antigen receptor signaling, crucial for NF-κB activation in lymphocytes.
• Malt1's proteolytic activity is known to cleave NF-κB inhibitors, but its broader physiological roles remain unclear.
• Mutations in Malt1 are frequently observed in human lymphoma, highlighting its importance in immune cell function and disease.

Purpose of the Study:

• To investigate the physiological functions of Malt1-protease activity in vivo.
• To elucidate the specific roles of Malt1 in lymphocyte development, activation, and immune regulation.
• To understand the consequences of Malt1 paracaspase inactivation on systemic immunity and potential pathologies.

Main Methods:

• Targeted inactivation of Malt1 paracaspase in a mouse model.
• Analysis of lymphocyte development and activation thresholds.
• Assessment of NF-κB signaling pathways and downstream targets, including mRNA stability regulators.
• Measurement of cytokine production, particularly interferon gamma (IFNγ).

Main Results:

• Malt1 paracaspase inactivation led to a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration.
• Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development.
• Malt1 cleaves mRNA stability regulators (Roquin-1, Roquin-2, Regnase-1), and its inactivation causes excessive IFNγ production by effector lymphocytes.
• Selective paracaspase blockage resulted in systemic immunity skewed toward autoinflammation.

Conclusions:

• Malt1 exhibits distinct threshold and modulatory functions controlling lymphocyte differentiation and activation.
• Malt1-protease activity is critical for preventing autoinflammation and maintaining immune homeostasis.
• Targeting Malt1 paracaspase activity offers insights into immune-mediated pathologies and potential therapeutic strategies.