Non-canonical NF-κB activation and abnormal B cell accumulation in mice expressing ubiquitin protein ligase-inactive c-IAP2

Chromosomal translocations between loci encoding malt1 and c-iap2 are common in malt lymphomas. the resulting fusion proteins lack the c-iap2 ring domain,the region responsible for its ubiquitin protein ligase (e3) activity. ectopic expression of the fusion protein activates the canonical nf-κb signaling cascade,but how it does so is controversial and how it promotes malt lymphoma is unknown. considering recent reports implicating c-iap1 and c-iap2 e3 activity in repression of non-canonical nf-κb signaling,we asked if the c-iap2/malt fusion protein can initiate non-canonical nf-κb activation. here we show that in addition to canonical activation,the fusion protein stabilizes nik and activates non-canonical nf-κb. canonical but not non-canonical activation depended on malt1 paracaspase activity,and expression of e3-inactive c-iap2 activated non-canonical nf-κb. mice in which endogenous c-iap2 was replaced with an e3-inactive mutant accumulated abnormal b cells with elevated non-canonical nf-κb and had increased numbers of b cells with a marginal zone phenotype,gut-associated lymphoid hyperplasia,and other features of malt lymphoma. thus,the c-iap2/ malt1 fusion protein activates nf-κb by two distinct mechanisms,and loss of c-iap2 e3 activity in vivo is sufficient to induce abnormalities common to malt lymphoma.