| First Author | Dai P | Year | 2009 |
| Journal | J Immunol | Volume | 182 |
| Issue | 6 | Pages | 3450-60 |
| PubMed ID | 19265123 | Mgi Jnum | J:145929 |
| Mgi Id | MGI:3836337 | Doi | 10.4049/jimmunol.0802260 |
| Citation | Dai P, et al. (2009) Modulation of TLR signaling by multiple MyD88-interacting partners including leucine-rich repeat Fli-I-interacting proteins. J Immunol 182(6):3450-60 |
| abstractText | Emerging evidences suggest TLR-mediated signaling is tightly regulated by a specific chain of intracellular protein-protein interactions, some of which are yet to be identified. Previously we utilized a dual-tagging quantitative proteomics approach to uncover MyD88 interactions in LPS-stimulated cells and described the function of Fliih, a leucine-rich repeat (LRR) protein that negatively regulates NF-kappaB activity. Here we characterize two distinct LRR-binding MyD88 interactors, LRRFIP2 and Flap-1, and found that both are positive regulators of NF-kappaB activity. Upon LPS stimulation, LRRFIP2 was also found to positively regulate cytokine production in macrophages, suggesting a functional role in TLR4-mediated inflammatory response. Furthermore, we observed that immediately following LPS stimulation both LRRFIP2 and Flap-1 compete with Fliih for interacting with MyD88 to activate the signaling. By using a novel multiplex quantitative proteomic approach, we found that at endogenous levels these positive and negative regulators interact with MyD88 in a timely and orderly manner to differentially mediate the NF-kappaB activity through the course of signaling from initiation to prolongation, and to repression. Based on these data, we describe a mechanistic model in which selective modulation of TLR signaling is achieved by temporal and dynamic interactions of MyD88 with its regulators. |
