Ubiquitination-Dependent Activation of IKK

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Ubiquitination-Dependent Activation of IKK

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Title: Ubiquitination-Dependent Activation of IKK
Author: Ea, Chee-Kwee
Abstract: Ubiquitination plays two different roles in the nuclear factor κΒ (NF-κΒ ) pathway, the traditional K48-linked polyubiquitination-mediated IκΒ degradation and the non-traditional K63-linked polyubiquitination-mediated IKK activation. TRAF6 is a RING domain ubiquitin ligase that mediates the activation of protein kinases such as TAK1 and IKK by promoting the formation of a unique polyubiquitin chain linked through lysine-63 of ubiquitin. Previous studies have suggested that the ubiquitin ligase and signaling activity of TRAF6 may be regulated by its oligomerization. However, it is not known whether there is an endogenous "oligomerizer" that regulates TRAF6 activity. TRAF-interacting protein with a forkhead-associated (FHA) domain (TIFA, also known as T2BP) is one of such TRAF6 "oligomerizers". Recombinant TIFA protein, but not TRAF6-binding defective mutant protein, can activate IKK in crude cytosolic extracts. Furthermore, TIFA activates IKK in an in vitro reconstitution system consisting of purified proteins including TRAF6, the TAK1 kinase complex and the ubiquitin conjugating enzyme complex Ubc13/Uev1A. Interestingly, a fraction of recombinant TIFA protein exists as high molecular weight oligomers, and only these oligomeric forms of TIFA can activate IKK. Importantly, TIFA induces the oligomerization and polyubiquitination of TRAF6, which leads to the activation of TAK1 and IKK through a proteasome-independent mechanism. The receptor interacting protein kinase 1 (RIP1) is essential for the activation of NF-κΒ in response to tumor necrosis factor a (TNFa) stimulation. RIP1 undergoes TNF-induced polyubiquitination at Lysine 377 in the intermediate domain and the polyubiquitination of RIP1 is required for proper signal transduction. Furthermore, when introducing RIPK377R mutant into RIP-/- Jurkat cells, it fails to restore TNF-dependent IKK activation, and these RIPK377R cells are sensitive to TNFa-induced cell death. In addition, TAK1 and IKK kinase complexes are not recruited to TNFR1 followed TNFa stimulation in the absence of RIP1 polyubiquitination. Moreover, TAB2 and NEMO bind to K63-linked polyubiquitin chains and function as receptors that bind polyubiquitinated RIP1. These results indicate a unique interaction between a polyubiquitinated protein and a polyubiquitin binding protein can trigger the activation of TAK1 and IKK.
URI: http://hdl.handle.net/2152.5/382
Date: 2005-12-19

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