Letter abstract
Nature Cell Biology 10, 1309 - 1317 (2008)
Published online: 19 October 2008 | doi:10.1038/ncb1789
IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-
B as well as cell survival and oncogenesis
Mads Gyrd-Hansen1,2,10, Maurice Darding1,10, Maria Miasari3, Massimo M. Santoro4,5, Lars Zender6, Wen Xue6,7, Tencho Tenev1, Paula C.A. da Fonseca8, Marketa Zvelebil1, Janusz M. Bujnicki9, Scott Lowe6, John Silke3 & Pascal Meier1
The covalent attachment of ubiquitin to target proteins influences various cellular processes, including DNA repair, NF-
B 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-
-induced apoptosis. Moreover, the UBA domain is required for XIAP and cIAP2–MALT1 to activate NF-B. Our data suggest that the UBA domain of cIAP2–MALT1 stimulates NF-B 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-B signalling and oncogenesis.
- The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK.
- Current address: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloees Vej 5, DK-2200 Copenhagen, Denmark.
- Department of Biochemistry, Level 4 RL Reid Building, La Trobe University, Victoria 3086, Australia.
- Molecular Biotechnology Center, University of Torino, Torino 10126, Italy.
- Department of Environmental and Life Sciences, University of Piemonte Orientale, Alessandria 15100, Italy.
- Cold Spring Harbor Laboratory, NY-11724, USA.
- Helmholtz Centre for Infection Research, Braunschweig 38124, Germany and Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany.
- Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK.
- International Institute of Molecular and Cell Biology in Warsaw, ul. Trojdena 4, 02-109 Warsaw, and Adam Mickiewicz University, ul. Umultowska 89, 61-614 Poznan, Poland.
- These authors contributed equally to this work.
Correspondence to: Pascal Meier1 e-mail: pmeier@icr.ac.uk
Correspondence to: Mads Gyrd-Hansen1,2,10 e-mail: mads.gyrd@bric.dk
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