Modulation of TLR signaling by multiple MyD88-interacting partners including leucine-rich repeat Fli-I-interacting proteins.

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.
Mesh Terms:
Animals, Binding, Competitive, Carrier Proteins, Cell Line, Cell Line, Tumor, Cytoskeletal Proteins, Humans, Macrophages, Mice, Mice, Inbred C3H, Microfilament Proteins, Myeloid Differentiation Factor 88, NF-kappa B, Protein Binding, RNA-Binding Proteins, Receptors, Cytoplasmic and Nuclear, Signal Transduction, Toll-Like Receptor 4
J. Immunol.
Date: Mar. 15, 2009
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