title: Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages.
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.
authors.affiliation: Bose Institute, Department of Chemistry, Kolkata 700 009, India.
authors.forename: Sushil Kumar
authors.initials: SK
authors.lastname: Pathak
authors.forename: Sanchita
authors.initials: S
authors.lastname: Basu
authors.forename: Kunal Kumar
authors.initials: KK
authors.lastname: Basu
authors.forename: Anirban
authors.initials: A
authors.lastname: Banerjee
authors.forename: Shresh
authors.initials: S
authors.lastname: Pathak
authors.forename: Asima
authors.initials: A
authors.lastname: Bhattacharyya
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
authors.forename: Manikuntala
authors.initials: M
authors.lastname: Kundu
authors.forename: Joyoti
authors.initials: J
authors.lastname: Basu
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D050835:Interferon Regulatory Factors; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D053592:Interleukin-1 Receptor-Associated Kinases; D051057:Proto-Oncogene Proteins c-akt