Mechanistic elucidation of novel CARD11 variants

In immunity, NF-KB signaling has an important role in regulating different functions in T and B cells. Many of the proteins involved in innate and adaptive immunity requires the formation of high order assemblies. The CARD11/BCL10/MALT1 (CBM) complex has a central role in mediating signaling in the cells, leading to NF-KB activation. CBM complex was shown to also form a high-order assembly, presented as filaments. Mutations in the proteins forming the CBM complex were shown to be directly associated with lymphomas.

CARD11 was also shown to be involved in alternative pathways in cells and therefore CARD11 was associated with different type of severe human disorders. CARD11 variants that exhibit gain of function were associated with B cell Expansion with NF-KB and T cell Anergy (BENTA) disease. By contrast, CARD11 loss of function variants were associated with atopic disease and presented severe, recalcitrant atopic dermatitis (AD). Our proposed collaborative study suggests providing mechanistic View of novel CARD11 variants by pursuing the following aims by utilizing genetic, biochemical, structural and cellular cutting-edge tools: 1) Aim 1 — identification and characterization of novel impactful CARD11 patients’ variants. 2) Aim 2 — Biochemical and cellular elucidation of CARD11 Variants. 3) Aim 3 — Structure determination of full-length WT CARD11 and impactful CARD11 GOF/LOF variants. Towards this important goal we already assessed ~ 28 CARD11 variants that will guide our biochemical and structural investigation. The successful accomplishment of the collaborative study between Snow and David labs will enable and inform development of novel treatment strategies for providing better treatment and care for the patients having these disorders and will open up new approaches for discovering new medicines for CARD11 patients.