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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.

Pubmed ID: 19265123


  • Dai P
  • Jeong SY
  • Yu Y
  • Leng T
  • Wu W
  • Xie L
  • Chen X


Journal of immunology (Baltimore, Md. : 1950)

Publication Data

March 15, 2009

Associated Grants

  • Agency: NIAID NIH HHS, Id: 1R01AI064806-01A2

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