Schematic diagram showing the structure of WT cIAP2 (A) and of the t(11;18)(q21;q21)-associated cIAP2-MALT1 fusion protein (B), as demonstrated in this issue of the JCI by Hu et al. (22). BCL10 can bind to the BIR region of WT cIAP2. As shown by Hu et al., the RING domain of cIAP2 has ubiquitin ligase (E3) activity. Because of BIR-mediated binding, cIAP2 leads to BCL10 ubiquitylation, a mechanism to regulate BCL10 activity after antigen receptor stimulation. The cIAP2-MALT1 fusion protein created by the t(11;18)(q21;q21) chromosomal translocation always lacks the RING domain of cIAP2, while it always contains the BIR domains (B). The cIAP2-MALT1 protein can still bind BCL10 via the BIR domains, but it is not able to ubiquitylate it, because of the lack of the RING domain. The intact BCL10 synergistically increases cIAP2-MALT1’s intrinsic capacity for NF-κB activation. It is still not clear why the BIR-mediated BCL10 binding would not affect the transfer of BCL10 from the nucleus to the cytoplasm, which would be mediated, as recently shown (23), by the nuclear export signals (NESs), present in the cIAP2-MALT1 fusion protein. The dashed lines show the most frequent breakpoint sites occurring in the t(11;18)(q21;q21) chromosomal translocation. Ub, ubiquitin.