| First Author | Conze DB | Year | 2010 |
| Journal | PLoS Biol | Volume | 8 |
| Issue | 10 | Pages | e1000518 |
| PubMed ID | 21048983 | Mgi Jnum | J:166899 |
| Mgi Id | MGI:4850180 | Doi | 10.1371/journal.pbio.1000518 |
| Citation | Conze DB, et al. (2010) Non-canonical NF-kappaB activation and abnormal B cell accumulation in mice expressing ubiquitin protein ligase-inactive c-IAP2. PLoS Biol 8(10):e1000518 |
| abstractText | 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-kappaB 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-kappaB signaling, we asked if the c-IAP2/MALT fusion protein can initiate non-canonical NF-kappaB activation. Here we show that in addition to canonical activation, the fusion protein stabilizes NIK and activates non-canonical NF-kappaB. Canonical but not non-canonical activation depended on MALT1 paracaspase activity, and expression of E3-inactive c-IAP2 activated non-canonical NF-kappaB. Mice in which endogenous c-IAP2 was replaced with an E3-inactive mutant accumulated abnormal B cells with elevated non-canonical NF-kappaB 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-kappaB by two distinct mechanisms, and loss of c-IAP2 E3 activity in vivo is sufficient to induce abnormalities common to MALT lymphoma. |
