IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-κB as well as cell survival and oncogenesis

A ubiquitin binding domain in the IAP proteins binds Lys 63-linked poly-ubiquitin chains and is essential for the oncogenic potential of cIAP. This domain is also required for activating NF-κB, possibly by binding poly-ubiquitinated NEMO. The covalent attachment of ubiquitin to target proteins influences various cellular processes, including DNA repair, NF-κB signalling and cell survival 1 . The most common mode of regulation by ubiquitin-conjugation involves specialized ubiquitin-binding proteins that bind to ubiquitylated proteins and link them to downstream biochemical processes. Unravelling how the ubiquitin-message is recognized is essential because aberrant ubiquitin-mediated signalling contributes to tumour formation 2 . Recent evidence indicates that inhibitor of apoptosis (IAP) proteins are frequently overexpressed in cancer and their expression level is implicated in contributing to tumorigenesis, chemoresistance, disease progression and poor patient-survival 3 . Here, we have identified an evolutionarily conserved ubiquitin-associated (UBA) domain in IAPs, which enables them to bind to Lys 63-linked polyubiquitin. We found that the UBA domain is essential for the oncogenic potential of cIAP1, to maintain endothelial cell survival and to protect cells from TNF-α-induced apoptosis. Moreover, the UBA domain is required for XIAP and cIAP2–MALT1 to activate NF-κB. Our data suggest that the UBA domain of cIAP2–MALT1 stimulates NF-κB signalling by binding to polyubiquitylated NEMO. Significantly, 98% of all cIAP2–MALT1 fusion proteins retain the UBA domain, suggesting that ubiquitin-binding contributes to the oncogenic potential of cIAP2–MALT1 in MALT lymphoma. Our data identify IAPs as ubiquitin-binding proteins that contribute to ubiquitin-mediated cell survival, NF-κB signalling and oncogenesis.