Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9

Boyoun Park, Melanie M. Brinkmann, Eric Spooner, Clarissa C. Lee, You Me Kim, Hidde L. Ploegh

Research output: Contribution to journalArticle

334 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1407-1414
Number of pages8
JournalNature Immunology
Volume9
Issue number12
DOIs
Publication statusPublished - 2008 Oct 20

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Toll-Like Receptor 9
Proteolysis
Cathepsin L
Toll-Like Receptors
DNA
Innate Immunity
Dendritic Cells
Immune System
Peptide Hydrolases
Cytokines
Ligands
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Park, Boyoun ; Brinkmann, Melanie M. ; Spooner, Eric ; Lee, Clarissa C. ; Kim, You Me ; Ploegh, Hidde L. / Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. In: Nature Immunology. 2008 ; Vol. 9, No. 12. pp. 1407-1414.
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Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. / Park, Boyoun; Brinkmann, Melanie M.; Spooner, Eric; Lee, Clarissa C.; Kim, You Me; Ploegh, Hidde L.

In: Nature Immunology, Vol. 9, No. 12, 20.10.2008, p. 1407-1414.

Research output: Contribution to journalArticle

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