Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages

Sushil Kumar Pathak; Sanchita Basu; Kunal Kumar Basu; Anirban Banerjee; Shresh Pathak; Asima Bhattacharyya; Tsuneyasu Kaisho; Manikuntala Kundu; Joyoti Basu

doi:10.1038/ni1468

Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages

Nat Immunol. 2007 Jun;8(6):610-8. doi: 10.1038/ni1468. Epub 2007 May 7.

Authors

Sushil Kumar Pathak¹, Sanchita Basu, Kunal Kumar Basu, Anirban Banerjee, Shresh Pathak, Asima Bhattacharyya, Tsuneyasu Kaisho, Manikuntala Kundu, Joyoti Basu

Affiliation

¹ Bose Institute, Department of Chemistry, Kolkata 700 009, India.

PMID: 17486091
DOI: 10.1038/ni1468

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

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Bacterial / metabolism*
Bacterial Proteins / metabolism*
Cell Line
Enzyme Activation
Humans
Interferon Regulatory Factors / metabolism
Interleukin-1 Receptor-Associated Kinases / metabolism
Interleukin-12 Subunit p40 / biosynthesis
Lipopolysaccharides / pharmacology
Macrophages / drug effects
Macrophages / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Mycobacterium tuberculosis / metabolism*
Myeloid Differentiation Factor 88 / metabolism
NF-kappa B / metabolism
Protein Binding
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction*
Time Factors
Toll-Like Receptor 2 / deficiency
Toll-Like Receptor 2 / genetics
Toll-Like Receptor 2 / metabolism*

Substances

Antigens, Bacterial
Bacterial Proteins
ESAT-6 protein, Mycobacterium tuberculosis
Interferon Regulatory Factors
Interleukin-12 Subunit p40
Lipopolysaccharides
Myeloid Differentiation Factor 88
NF-kappa B
Toll-Like Receptor 2
Interleukin-1 Receptor-Associated Kinases
Proto-Oncogene Proteins c-akt