Recruitment of the Linear Ubiquitin Chain Assembly Complex Stabilizes the TNF-R1 Signaling Complex and Is Required for TNF-Mediated Gene Induction
Copyright policy )Recruitment of the Linear Ubiquitin Chain Assembly Complex Stabilizes the TNF-R1 Signaling Complex and Is Required for TNF-Mediated Gene Induction
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, and is required for efficient TNF-induced activation of NF-kappaB 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.
- Catholic University of the Sacred Heart Italy
- Hammersmith Hospital United Kingdom
- Imperial College London United Kingdom
- German Cancer Research Center Germany
- Imperial College Healthcare NHS Trust United Kingdom
Ubiquitin-Protein Ligases, Proliferation and Death, Apoptosis, Cell Line, Inhibitor of Apoptosis Proteins, Mice, 0601 (four-digit-FOR), Animals, Humans, Molecular Biology, Tumor Necrosis Factor-alpha, Ubiquitin, GTPase-Activating Proteins, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, NF-kappa B, Cell Biology, U937 Cells, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Death Domain Protein, 060103 Cell Development, Gene Expression Regulation, Receptors, Tumor Necrosis Factor, Type I, MOLIMMUNO; PROTEINS; SIGNALING; Animals; Apoptosis; Cell Line; GTPase-Activating Proteins; HeLa Cells; Humans; Inhibitor of Apoptosis Proteins; Intracellular Signaling Peptides and Proteins; JNK Mitogen-Activated Protein Kinases; Mice; NF-kappa B; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; TNF Receptor-Associated Death Domain Protein; TNF Receptor-Associated Factor 2; Tumor Necrosis Factor-alpha; U937 Cells; Ubiquitin; Ubiquitin-Protein Ligases; Gene Expression Regulation; Molecular Biology; Cell Biology, HeLa Cells, Signal Transduction
Ubiquitin-Protein Ligases, Proliferation and Death, Apoptosis, Cell Line, Inhibitor of Apoptosis Proteins, Mice, 0601 (four-digit-FOR), Animals, Humans, Molecular Biology, Tumor Necrosis Factor-alpha, Ubiquitin, GTPase-Activating Proteins, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, NF-kappa B, Cell Biology, U937 Cells, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Death Domain Protein, 060103 Cell Development, Gene Expression Regulation, Receptors, Tumor Necrosis Factor, Type I, MOLIMMUNO; PROTEINS; SIGNALING; Animals; Apoptosis; Cell Line; GTPase-Activating Proteins; HeLa Cells; Humans; Inhibitor of Apoptosis Proteins; Intracellular Signaling Peptides and Proteins; JNK Mitogen-Activated Protein Kinases; Mice; NF-kappa B; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; TNF Receptor-Associated Death Domain Protein; TNF Receptor-Associated Factor 2; Tumor Necrosis Factor-alpha; U937 Cells; Ubiquitin; Ubiquitin-Protein Ligases; Gene Expression Regulation; Molecular Biology; Cell Biology, HeLa Cells, Signal Transduction
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