Activation Inhibition Indirectly activation Translocation Phosphorylation P Activation Inhibition Translocation Phosphorylation Ubiquitin Ub P Target Gene Target Gene Target Gene Canonical Noncanonical Proteasome DAG Degradation TGF-βReceptor RTK GPCR TNFR TCR BCR TLR IL-1R CD40 BAFFR TRADD RIPK1 IKKα IKKα IKKα IKKβ NEMO SYK ZAP70 LYN LCK IκBα IκBα IκBα NIK TAK1 PKC TAB2/3 HOIP HOIL1 SHARPIN β-TrCP BCL10 CARD11 MALT1 cIAP1/2 cIAP1/2 TRAF2/3 cIAP1/2 TRAF2/3 TRAF6 TRAF6 BTK LAT PLCG2 PLCG1 MyD88 MyD88 IRAK1/4 IRAK1/4 TRAF2/5 NF-κBp50 NF-κBp65 NF-κBp50 NF-κBp50 NF-κBp65 NF-κBp50 NF-κBp65 NF-κBp52 NF-κBp100 RelB RelB NF-κBp52 RelB c-Rel NF-κBp50 c-Rel NF-κBp50 c-Rel P P P P P P Ub Ub Ub Cytoplasm CBM complex LUBAC Nucleus