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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 . |
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