Abstract
Expression of early secreted antigenic target protein 6 (ESAT-6) by Mycobacterium tuberculosis is associated with lower innate immune responses to infection. Here we show that ESAT-6 inhibited activation of transcription factor NF-kappaB and interferon-regulatory factors (IRFs) after Toll-like receptor (TLR) signaling; inhibition of TLR signaling by ESAT-6 required the kinase Akt. Direct binding of ESAT-6 to TLR2 activated Akt and prevented interaction between the adaptor MyD88 and 'downstream' kinase IRAK4, thus abrogating NF-kappaB activation. The six carboxy-terminal amino acid residues of ESAT-6 were required and sufficient for the TLR2-mediated inhibitory effect. A critical function for the carboxy-terminal peptide of ESAT-6 in restricting MyD88-dependent TLR signaling emphasizes the possibility that mimetic inhibitory peptides could be used to restrict innate immune responses in situations in which prolonged TLR signaling has deleterious effects.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Bacterial / metabolism*
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Bacterial Proteins / metabolism*
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Cell Line
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Enzyme Activation
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Humans
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Interferon Regulatory Factors / metabolism
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Interleukin-1 Receptor-Associated Kinases / metabolism
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Interleukin-12 Subunit p40 / biosynthesis
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects
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Macrophages / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mycobacterium tuberculosis / metabolism*
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Myeloid Differentiation Factor 88 / metabolism
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NF-kappa B / metabolism
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Protein Binding
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction*
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Time Factors
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Toll-Like Receptor 2 / deficiency
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / metabolism*
Substances
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Antigens, Bacterial
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Bacterial Proteins
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ESAT-6 protein, Mycobacterium tuberculosis
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Interferon Regulatory Factors
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Interleukin-12 Subunit p40
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Lipopolysaccharides
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Myeloid Differentiation Factor 88
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NF-kappa B
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Toll-Like Receptor 2
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Interleukin-1 Receptor-Associated Kinases
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Proto-Oncogene Proteins c-akt