Ubiquitination of ECSIT is crucial for the activation of p65/p50 NF-κBs in Toll-like receptor 4 signaling.

Recent evidence shows that evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6) ubiquitinated, and contributes to bactericidal activity during Toll-like receptor (TLR) signaling. Here, we first report a new regulatory role for ECSIT in TLR4 signaling. On TLR4 stimulation, endogenous ECSIT ...
forms a molecular complex if p65/p50 NF- Κ: Bs. Our biochemical studies show that ECSIT specifically interacted with p65/p50 NF- Κ: Bs, which colocalized in the nucleus. Interestingly, these effects were critically dependent on ubiquitination of the ECSIT lysine (K) 372 residue. K372A mutant ECSIT did not interact with p65/p50 NF- Κ: Bs, and markedly attenuated nuclear colocalization. Additionally, ECSIT-knockdown THP-1 cells could not activate NF- Κ: B DNA-binding activities of p65 and p50, production of proinflammatory cytokines, and NF- Κ: B-dependent gene expression in response to TLR4 stimulation. However, these activities were markedly restored by expressing the wild-type ECSIT protein but not the K372A mutant ECSIT protein. These date strongly suggest that the ubiquitination of ECSIT might have the regulation of NF- Κ: B activity in TLR4 signaling.
Mol. Biol. Cell
Date: Oct. 29, 2014
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