Potentiation of Noncanonical NF- B Signaling and Marginal Zone B Cell Expansion by CARD11-mediated Regulation of p100 Processing

Caspase recruitment domain-containing protein 11 (CARD11) is a multi-domain scaffolding protein critical for the adaptive immune response that is required for antigen receptor signaling to canonical NF-kB, mTOR, JNK, and AKT. Oncogenic gain-of-function (GOF) CARD11 mutants, implicated in a variety of lymphomas, bypass normal regulation and signal constitutively. In a mouse model expressing the lymphoma-associated GOF mutation CARD11 C49Y, we observed splenomegaly concomitant with B cell expansion that was most pronounced for Marginal Zone (MZ) B cells. CARD11C49Y/C49Y MZ B cells exhibited enhanced cell-autonomous survivability and elevated basal levels of the precursor NF-kB subunit p100, which was inducibly processed, leading to elevated nuclear p52 levels in response to BAFF. We show in a heterologous assay that active CARD11 variants can inhibit basal NIK-induced p100 processing to p52 independently of their ability to activate canonical NF-kB. Our results reveal an unexpected ability of CARD11 GOF mutants to potentiate the noncanonical NF-kB pathway through p100 accumulation, which likely contributes to the dysregulated B cell expansion observed in lymphomas that harbor CARD11 GOF variants.