Potentiation of noncanonical NF-κB signaling and marginal zone B cell expansion by CARD11-mediated regulation of p100 processing

The signaling scaffold CARD11 is critical for adaptive immunity and antigen receptor signaling to canonical nuclear factor κB (NF-κB), mTOR, JNK, and AKT. Oncogenic gain-of-function (GoF) CARD11 mutants, implicated in a variety of lymphomas, bypass regulation and signal constitutively. In mice expressing the lymphoma-associated mutation CARD11 C49Y, we observe B cell expansion that is most impressive for marginal zone (MZ) B cells. CARD11^C49Y/C49Y MZ B cells exhibit enhanced cell-autonomous survivability and elevated basal levels of the precursor NF-κB subunit p100, which is inducibly processed, leading to elevated nuclear p52 levels in response to B cell activating factor (BAFF). We show that active CARD11 variants can inhibit basal NIK-induced p100 processing to p52 independently of their ability to activate canonical NF-κB. Our results reveal an unexpected ability of activated CARD11 to potentiate the noncanonical NF-κB pathway through p100 accumulation, which likely contributes to both normal B cell homeostasis and the dysregulated proliferation of lymphomas that harbor CARD11 GoF variants.