TLR processing at low pH

Stable Identifier
Reaction [transition]
Homo sapiens
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Endosome maturation (acidification) is required for both the activation of TLR9 and TLR7 through proteolytic cleavage and the disassembly of pathogens, thereby releasing the TLR ligands within them. TLR7 and TLR9 are cleaved within their ectodomains by pH-sensitive cysteine endopeptidases. Cathepsins (CTS) B, K, L, and S, and asparagine endopeptidase (AEP, also known as legumain) have been implicated in endolysosomal TLR processing, however, several groups have reported somewhat controversial results on the role of specific proteases (Matsumoto F et al 2008, Park B et al 2008, Ewald SE et al 2008, Ewald SE et al 2011, Sepulveda FE et al 2009).

One study showed that TLR9 proteolysis is a multistep process with the initial cleavage that can be mediated by AEP or multiple members of the cathepsin family. The second event is mediated exclusively by cathepsins. TLR7 and TLR3 were reported to be cleaved in a similar manner (Ewald SE et al 2011). Cleavage of TLR3 is not shown in this reaction, since other studies demonstrated that the N-terminal region of TLR3 ectodomain was implicated in ligand binding, suggesting that TLR3 may function as a full-length receptor (Liu L et al 2008, Tokisue T et al 2008).

Both full-length receptor and cleaved fragment corresponding to the C-terminal part of TLR9 were capable to bind ligand, however only the processed form (TLR9 C-ter, aa 471-1032) was shown to bind MyD88 and induce signaling in different mouse cells (Ewald SE et al 2008).

Literature References
PubMed ID Title Journal Year
18931679 Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9

Ploegh, HL, Lee, CC, Spooner, E, Kim, YM, Park, B, Brinkmann, MM

Nat Immunol 2008
18820679 The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor

Barton, GM, Wickliffe, KE, Ewald, SE, Chapman, HA, Lau, L, Lee, BL, Shi, GP

Nature 2008
18166152 Cathepsins are required for Toll-like receptor 9 responses

Matsumoto, F, Miyake, K, Akashi-Takamura, S, Kusumoto, Y, Tanimura, N, Kobayashi, T, Fukui, R, Saitoh, S, Konno, K

Biochem Biophys Res Commun 2008
21402738 Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase

Barton, GM, Lee, J, Ewald, SE, Wang, M, Bogyo, M, Engel, A

J Exp Med 2011
Catalyst Activity

cysteine-type endopeptidase activity of Legumain/Cathepsins [endolysosome lumen]

This event is regulated
Positively by
Orthologous Events
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