Activation of the IκB Kinases by RIP via IKKγ/NEMO-mediated Oligomerization*

By J. Poyet, S. Srinivasula, Jun-hsiang Lin, T. Fernandes-Alnemri, S. Yamaoka, P. Tsichlis, E. Alnemri. Journal of Biological Chemistry, 2000

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To understand the mechanism of activation of the IκB kinase (IKK) complex in the tumor necrosis factor (TNF) receptor 1 pathway, we examined the possibility that oligomerization of the IKK complex triggered by ligand-induced trimerization of the TNF receptor 1 complex is responsible for activation of the IKKs. Gel filtration analysis of the IKK complex revealed that TNFα stimulation induces a large increase in the size of this complex, suggesting oligomerization. Substitution of the C-terminal region of IKKγ, which interacts with RIP, with a truncated DR4 lacking its cytoplasmic death domain, produced a molecule that could induce IKK and NF-κB activation in cells in response to TRAIL. Enforced oligomerization of the N terminus of IKKγ or truncated IKKα or IKKβ lacking their serine-cluster domains can also induce IKK and NF-κB activation. These data suggest that IKKγ functions as a signaling adaptor between the upstream regulators such as RIP and the IKKs and that oligomerization of the IKK complex by upstream regulators is a critical step in activation of this complex.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/41aeced65b8be2738175dc0427b587cf652bfa87

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Citations in the corpus

Requirement of Hsp90 activity for IκB kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-κB activation (2004, background): “Since constitutive IKK and NF-kB is Oncogene observed in a number of malignancies (Rayet and Gelinas, 1999), the block of NF-kB activation by GA may be a critical aspect of the antitumor activity of this class of drugs.”
Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. (2003, unknown): “…leads not only to the recruitment and assembly of TRADD, RIP1 and TRAF2, but also of components of the downstream NF-B machinery, such as I-B, the protein kinases IKK, and the scaffold protein IKK in se rm -0 05 27 10 5, v er si on 1 - 18 O ct 2 01 0 (Poyet et al., 2000; Zhang et al., 2000).”
De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling (2004, background): “, possibly through recruiting, oligomerizing and thereby promoting activation of the IκB kinase (IκK) comple”