Journal article
Recruitment of the Linear Ubiquitin Chain Assembly Complex Stabilizes the TNF-R1 Signaling Complex and Is Required for TNF-Mediated Gene Induction
TL Haas, CH Emmerich, B Gerlach, AC Schmukle, SM Cordier, E Rieser, R Feltham, J Vince, U Warnken, T Wenger, R Koschny, D Komander, J Silke, H Walczak
Molecular Cell | CELL PRESS | Published : 2009
Abstract
TNF is a key inflammatory cytokine. Using a modified tandem affinity purification approach, we identified HOIL-1 and HOIP as functional components of the native TNF-R1 signaling complex (TNF-RSC). Together, they were shown to form a linear ubiquitin chain assembly complex (LUBAC) and to ubiquitylate NEMO. We show that LUBAC binds to ubiquitin chains of different linkage types and that its recruitment to the TNF-RSC is impaired in TRADD-, TRAF2-, and cIAP1/2- but not in RIP1- or NEMO-deficient MEFs. Furthermore, the E3 ligase activity of cIAPs, but not TRAF2, is required for HOIL-1 recruitment to the TNF-RSC. LUBAC enhances NEMO interaction with the TNF-RSC, stabilizes this protein complex, a..
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Awarded by Medical Research Council
Funding Acknowledgements
We thank M.R. Sprick, M. Leverkus, P.H. Krammer, Y. Kulathu, and all members of the Walczak Lab for helpful discussions; D. Brenner, R. Arnold, and M. Li Weber for the gift of plasmids; S. Wandschneider and M. Schnolzer for MS analysis early in the project; M. Pasparakis for NEMO- and TRADD-deficient MEFs; H. Nakano for TRAF2/5 double knockout MEFs; M. Kelliher for the gift of RIP1 knockout mice; P. Seneci and L. Manzoni for the IAP inhibitor SM-164 (SMAC059); and C. Rappi for technical assistance. H.W. is founder, shareholder, and scientific advisor of Apogenix GmbH. J.S. is a consultant to TetraLogic Pharmaceuticals and funded by the NHMRC (433013, 541901, and 541902). T.L.H., E.R., and H.W. are funded by the EU Marie Curie Research Training Network "ApopTrain."