TRIAD3 (F1Z2P) Rabbit mAb #65255

The role of the innate immune response is to limit the spread of infectious pathogens. Toll-like receptor (TLR) activation results in pro-inflammatory responses that combat infection (1-4). Although TLR signaling generates inflammation to help clear infection, this process can also damage host tissues. It is, therefore, important for cells to have strictly regulated TLR responses. TLRs contain a cytoplasmic Toll/Interleukin-1 receptor (TIR) domain, which is necessary for recruiting proteins involved in regulating TLR signaling. E3 ubiquitin-protein ligase RNF216 (TRIAD3) was first discovered by utilizing a yeast two-hybrid screen (1-4); it was shown that TIR domains of multiple TLRs (TLR3, TLR4, TLR5, and TLR9) bind TRIAD3 (1).

TRIAD3 is a ubiquitin-protein ligase that promotes ubiquitination and proteolytic degradation of multiple TLRs, acting as a negative regulator of their signaling activation (1-4). In addition, TRIAD3 interacts and promotes downregulation of two TIR domain-containing adapter molecules, TIR domain-containing adapter-inducing IFN-β (TRIF) and TRIF-related TIR domain-containing adapter protein (TIRAP) (4). Moreover, TRIAD3 has been shown to act as a negative regulator of TNF-α signaling via its interaction with RIP1, effectively impeding RIP1-mediated NF-κB activation (5).

TRIAD3 has recently been shown to play a role in slowing cardiac hypertrophy by catalyzing ubiquitination-mediated degradation of TLR4 and TLR9, leading to reduced NF-κB pathway activation (6). TRIAD3 has also been shown to mediate autophagy in neurodegenerative diseases. (5,7). In vivo studies show that TRIAD3 decreases the accumulation of phosphorylated tau protein in mouse models. Mutations in TRIAD3 lead to increased accumulation of phosphorylated tau and neurodegenerative disease (7).