Ctenopharyngodon idella Tollip regulates MyD88-induced NF-κB activation.

Abstract Toll-interacting protein (Tollip) and MyD88 are key components of the TLR/IL-1R signaling pathway in mammals. MyD88 is known as a universal adaptor protein involving in TLR/IL-1R-induced NF-κB activation. Tollip is a crucial negative regulator of TLR-mediated innate immune responses. Previous studies have demonstrated that teleost Tollip served as a negative regulator of MyD88-dependent TLR signaling pathway. However, the mechanism is still unclear. In particular, the effect of TBD, C2, and CUE domains of Tollip on MyD88-NF-κB signaling pathway remains to be elucidated. In this study, we found that the response of grass carp Tollip (CiTollip) to LPS stimulation was faster and stronger than that of poly I:C treatment, and CiTollip diminished the expression of tnf-α induced by LPS. Further assays indicated that except for the truncated mutant of △CUE2 (1–173 aa), wild type CiTollip and other truncated mutants (△N-(52–276 aa), △C2-(173–276 aa) and △CUE1-(1–231 aa)) could associate with MyD88 and negatively regulate MyD88-induced NF-κB activation. It suggested that the C-terminal (173–276 aa), in particular the connection section between C2 and CUE domains (173–231 aa), played a pivotal role in suppressing MyD88-induced activation of NF-κB.