2 research outputs found
IAPs CARRY AN EVOLUTIONARILY CONSERVED UBIQUITIN-BINDING DOMAIN THAT IS INDISPENSABLE FOR NF-KB REGULATION AND CELL SURVIVAL.
The covalent attachment of ubiquitin to target proteins
influences various cellular processes, including DNA repair,
NF-\u3baB signalling and cell survival1. 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 formation2. 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-survival3. 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-\u3b1-induced apoptosis. Moreover,
the UBA domain is required for XIAP and cIAP2\u2013MALT1 to
activate NF-\u3baB. Our data suggest that the UBA domain of
cIAP2\u2013MALT1 stimulates NF-\u3baB signalling by binding to
polyubiquitylated NEMO. Significantly, 98% of all cIAP2\u2013
MALT1 fusion proteins retain the UBA domain, suggesting
that ubiquitin-binding contributes to the oncogenic potential
of cIAP2\u2013MALT1 in MALT lymphoma. Our data identify IAPs
as ubiquitin-binding proteins that contribute to ubiquitinmediated
cell survival, NF-\u3baB signalling and oncogenesis