Recruitment of the Linear Ubiquitin Chain Assembly Complex Stabilizes the TNF-R1 Signaling Complex and Is Required for TNF-Mediated Gene Induction

Tobias Longin Haas, Christoph H. Emmerich, Björn Gerlach, Anna C. Schmukle, Stefanie M. Cordier, Eva Rieser, Rebecca Feltham, James Vince, Uwe Warnken, Till Wenger, Ronald Koschny, David Komander, John Silke, Henning Walczak

Research output: Contribution to journalArticle

491 Citations (Scopus)

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, and is required for efficient TNF-induced activation of NF-κB 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. © 2009 Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)831-844
Number of pages14
JournalMolecular Cell
Volume36
DOIs
Publication statusPublished - 2009

Keywords

  • Animals
  • Apoptosis
  • Cell Biology
  • Cell Line
  • GTPase-Activating Proteins
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases
  • MOLIMMUNO
  • Mice
  • Molecular Biology
  • NF-kappa B
  • PROTEINS
  • Receptors, Tumor Necrosis Factor, Type I
  • SIGNALING
  • Signal Transduction
  • TNF Receptor-Associated Death Domain Protein
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • U937 Cells
  • Ubiquitin
  • Ubiquitin-Protein Ligases

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