Pathogenic CARD11 mutations affect B cell development and differentiation through a noncanonical pathway.

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Pathogenic CARD11 mutations are linked to immune disorders via aberrant nuclear factor κB (NF-κB) activation.
• The existence of NF-κB-independent regulatory mechanisms in CARD11 mutation pathogenesis remains unclear.

Purpose of the Study:

• To investigate the NF-κB-independent regulatory role of CARD11 in B cell signaling.
• To elucidate the function of CARD11 in the AKT-FOXO1 signaling axis.

Main Methods:

• Utilized three distinct genetic mouse models: Card11 knockout (KO), CARD11 E134G point mutation (BENTA disease), and CARD11 K215M oncogenic mutation.
• Analyzed NF-κB activation, AKT-FOXO1 signaling, and B cell development and differentiation in these models.

Main Results:

• CARD11 functions as a negative regulator of the AKT-FOXO1 pathway, independent of NF-κB.
• Both Card11 KO and the E134G mutant exhibit exacerbated AKT activation and reduced FOXO1 in B cells.
• The K215M mutant demonstrates a stronger inhibitory effect on AKT and stabilizes FOXO1, impacting B cell development differently than E134G.

Conclusions:

• CARD11 plays a critical role in regulating the AKT/FOXO1 signaling pathway in B cells, beyond its known role in NF-κB activation.
• Pathogenic CARD11 mutations impact this noncanonical regulatory function, highlighting its significance in immunological disorders.