| Tax1-binding protein (TAX1BP) 1 is an essential regulator of innate immunity and was originally identified in a yeast two-hybrid screen as a human T-lymphotropic virus Type 1 (HTLV-1) Tax1-binding protein and named TXBP151. Independently, TAX1BP1 was discovered in yeast two-hybrid screens that sought to identify novel binding partners of A20 and TRAF6, where it was named T6BP. Two human TAX1BP1 transcripts encoding modular proteins of 747 and 789 amino acids have been identified. The N-terminal region of TAX1BP1 possesses a SKIP carboxyl homology (SKITCH) domain and a 14-3-3 binding motif. The central region of TAX1BP1 harbors coiled-coil structures and helix-loop-helix regions that are thought to promote the formation of TAX1BP1 homodimers. The TAX1BP1 C-terminal region posesses zinc finger domains that function as novel ubiquitin-binding domains and allow for complex formation with K63-ubiquitinated RIP1 and TRAF6 as well as the E3 ubiquitin ligase ITCH. One of the major physiologic roles of TAX1BP1 is to serve as an essential component of a negative feedback loop aimed at restraining canonical NF-κB-mediated proinflammatory signaling cascades initiated by TNF and IL-1. It is likely that TAX1BP1 functions as a ubiquitin-binding adaptor protein that inducibly recruits A20 to a complex consisting, in part, of K63-ubiquitinated TRAF6, RIP1, and their cognate E2 conjugating enzyme, thus allowing for A20-mediated ubiquitin-editing and termination of NF-κB signaling. A recent report identified IKKα as a novel regulator of TAX1BP1 function and demonstrated that IKKα-dependent phosphorylation of TAX1BP1 at Ser593 and Ser624 in response to TNF and IL-1 is critical for its ability to orchestrate formation of the A20 ubiquitin-editing complex involved in termination of NF-κB signaling. |
