Description
A20, also referred to as TNF-alpha-induced protein 3 (TNFAIP3), is cytokine-inducible protein that functions to inhibit apoptosis and activate NF-kappaB (1, 2). It was first identified as a TNF-alpha inducible primary response gene in human umbilical vein endothelial cells, and encodes a 790-amino acid protein containing seven Cys2/Cys2-zinc finger motifs (3). Constitutive expression of A20 is observed in lymphoid tissues (4), but it is transiently expressed in a variety of cell types in response to inflammatory signals such as TNF-alpha (3, 5), IL-1 (3, 5), phorbol esters (6), and LPS (7). Expression of A20 can confer resistance to apoptosis and NF-kappaB activation triggered by these signals, probably through interference with TRAF (TNF receptor associated factor) family members (8, 9), and interaction with the NF-kappaB inhibiting protein ABIN (10). Studies also show that A20 contains site-specific ubiquitin modifying activity that can contribute to its biological functions (11, 12). The amino-terminus of A20 contains de-ubiquitinating (DUB) activity for Lys63 branches, such as those found in TRAF6 and RIP, while the carboxyl-terminus contains ubiquitin ligase (E3) activity for Lys48 branches of the same substrates and leads to their degradation (12)