Pathak Sushil Kumar, Basu Sanchita, Basu Kunal Kumar, Banerjee Anirban, Pathak Shresh, Bhattacharyya Asima, Kaisho Tsuneyasu, Kundu Manikuntala, Basu Joyoti
Bose Institute, Department of Chemistry, Kolkata 700 009, India.
Nat Immunol. 2007 Jun;8(6):610-8. doi: 10.1038/ni1468. Epub 2007 May 7.
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.
结核分枝杆菌早期分泌抗原靶蛋白6（ESAT-6）的表达与对感染的较低固有免疫反应相关。我们在此表明，ESAT-6在Toll样受体（TLR）信号传导后抑制转录因子核因子κB（NF-κB）和干扰素调节因子（IRF）的激活；ESAT-6对TLR信号传导的抑制需要激酶Akt。ESAT-6与TLR2的直接结合激活了Akt，并阻止了接头蛋白髓样分化因子88（MyD88）与“下游”激酶白细胞介素-1受体相关激酶4（IRAK4）之间的相互作用，从而消除了NF-κB的激活。ESAT-6的六个羧基末端氨基酸残基对于TLR2介导的抑制作用是必需且足够的。ESAT-6羧基末端肽在限制MyD88依赖性TLR信号传导中的关键功能强调了在TLR信号传导延长具有有害作用的情况下，模拟抑制肽可用于限制固有免疫反应的可能性。
