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. Author manuscript; available in PMC: 2014 Apr 1.
Published in final edited form as: For Immunopathol Dis Therap. 2013 Apr 1;4(2):93–110. doi: 10.1615/ForumImmunDisTher.2013008408

FIGURE 1.

FIGURE 1

TNFAIP3/A20 regulates NF-κB through both deubiquitinase and E3 ligase activities. (A) Upon engagement of TNFR1, clAP1/2 and TRAF2 promote the K63 ubiquitination of RIP1 while LUBAC promotes the linear ubiquitination of the IKK complex. These are brought together, in part, through the actions of the ubiquitin-binding adaptors TAB1 and TAB2. TAK interacts with TAB1 and TAB2 and phosphorylates IKKβ thus activating the IKK complex and initiating the NF-κB activation process. (B) TNFAIP3 (labeled as A20), functioning as a deubiquitinase, removes the K63 ubiquitin chain from RIP1 thus destabilizing the complex and blocking the ability of TAK to phosphorylation IKKβ. (C) Subsequently, TNFAIP3/A20, functioning as an E3 ligase, places K48 ubiquitin chains on RIP1 thus targeting it for proteasomal degradation. In addition, TNFAIP3/A20 escorts TRAF2 to the lysosome (in an ubiquitin-independent manner) where it is degraded as well.