Flightless I homolog negatively modulates the TLR pathway.
To date, much of our knowledge about the signaling networks involved in the innate immune response has come from studies using nonphysiologic model systems rather than actual immune cells. In this study, we used a dual-tagging proteomic strategy to identify the components of the MyD88 signalosome in murine macrophages stimulated with lipid A. This systems approach revealed 16 potential MyD88-interacting partners, one of which, flightless I homolog (Fliih) was verified to interact with MyD88 and was further characterized as a negative regulator of the TLR4-MyD88 pathway. Conversely, a reduction in endogenous Fliih by small-interfering RNA enhanced the activation of NF-kappaB, as well as cytokine production by LPS. Results from immunoprecipitation and a two-hybrid assay further indicated that Fliih directly interfered with the formation of the TLR4-MyD88 signaling complex. These results in turn suggest a new basis for the regulation of the TLR pathway by Fliih.
Wang
Tianyi
T
Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Chuang
Tsung-Hsien
TH
Ronni
Tapani
T
Gu
Sheng
S
Du
Yu-Chun
YC
Cai
Hong
H
Sun
Hui-Qiao
HQ
Yin
Helen L
HL
Chen
Xian
X
D000199:Actins / Q000737:chemistry / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015534:Trans-Activators
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000609263:FlII protein, mouse; C507779:MYD88 protein, human; D008840:Microfilament Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015534:Trans-Activators