Article abstract
Nature Immunology 9, 1407 - 1414 (2008)
Published online: 19 October 2008 | doi:10.1038/ni.1669
Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9
Boyoun Park1, Melanie M Brinkmann1, Eric Spooner1, Clarissa C Lee1, You-Me Kim2 & Hidde L Ploegh1
Abstract
Toll-like receptors (TLRs) activate the innate immune system in response to pathogens. Here we show that TLR9 proteolytic cleavage is a prerequisite for TLR9 signaling. Inhibition of lysosomal proteolysis rendered TLR9 inactive. The carboxy-terminal fragment of TLR9 thus generated included a portion of the TLR9 ectodomain, as well as the transmembrane and cytoplasmic domains. This cleavage fragment bound to the TLR9 ligand CpG DNA and, when expressed in Tlr9-/- dendritic cells, restored CpG DNA–induced cytokine production. Although cathepsin L generated the requisite TLR9 cleavage products in a cell-free in vitro system, several proteases influenced TLR9 cleavage in intact cells. Lysosomal proteolysis thus contributes to innate immunity by facilitating specific cleavage of TLR9.
- Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02115, USA.
- Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
Correspondence to: Hidde L Ploegh1 e-mail: ploegh@wi.mit.edu
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