期刊
MOLECULAR CELL
卷 36, 期 5, 页码 831-844出版社
CELL PRESS
DOI: 10.1016/j.molcel.2009.10.013
关键词
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资金
- NHMRC [433013, 541901, 541902]
- EU
- Cancer Research UK [10950] Funding Source: researchfish
- Medical Research Council [MC_U105192732] Funding Source: researchfish
- MRC [MC_U105192732] Funding Source: UKRI
TNF is a key inflammatory cytokine. Using a modified tandem affinity purification approach, we identified HOIL-1 and HOW 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, and is required for efficient TNF-induced activation of NF-kappa B and JNK, resulting in apoptosis inhibition. Finally, we demonstrate that sustained stability of the TNF-RSC requires LUBAC's enzymatic activity, thereby adding a third form of ubiquitin linkage to the triggering of TNF signaling by the TNF-RSC.
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