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

346 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

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this