Intacellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA

Speaker: 羅志文                    Date: 02/15/2006; 13:10-14:00

Commentator: 凌斌 老師             Place: Room 601

Abstract:

  Function characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system to detect invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathway and triggers further immune responses. Different members of the TLR family have very distinct functions in host defense, and their individual characteristics are also different.¹ The evolutionary logic between TLR functions and characteristics is unclear and represents one of the most fundamental aspects of TLR biology. In this paper, the authors examined the function of subcellular localization for TLR9.² First, they found that transmembrane region determines TLR cellular localization and constructed a chimeric TLR9 where the ectodomain of TLR9 was fused to the transmembrane and cytosolic domains of TLR4. This chimeric TLR9, which localizes to cell surface, can recognize CpG DNA at the cell surface but cannot sense viral DNA. Furthermore, they demonstrated that chimeric TLR9 can recognize self DNA, which dose not stimulate wild-type TLR9, and proposed that normally DNase I in the serum degrades extracellular self DNA before self DNA can access the intracellular DNA compartment. These results suggest that the intracellular localization of TLR9 is not required for ligand recognition but controls access of the receptor to different sources of DNA. This mechanism is probably critical for the proper discrimination between self- or foreign-derived nucleic acid.³

References:

1.      Takeda K and Akira S. Toll-like receptors in innate immunity. Int. Immunol. 17:1-14, 2005

2.      Latz E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. 5:190-8, 2004

3.      Barton GM, Kagan JC, and Medzhitov R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat. Immunol. 7:49-56, 2006