Critical Role for Asparagine Endopeptidase in Endocytic Toll-like Receptor Signaling in Dendritic Cells
| Autor: | Fernando E. Sepulveda, Bénédicte Manoury, Renaud Colisson, Sebastian Amigorena, Ana-Maria Lennon-Duménil, Lea Heslop, Sophia Maschalidi, Cristina Ghirelli, Lucien Cabanie, Emna Sakka |
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| Rok vydání: | 2009 |
| Předmět: |
Mice
Knockout Toll-like receptor Endosome Endocytic cycle Immunology TLR9 chemical and pharmacologic phenomena hemic and immune systems TLR7 Dendritic Cells Biology Cathepsins Endopeptidase Proinflammatory cytokine Cell biology Cysteine Endopeptidases Mice Infectious Diseases CELLIMMUNO Toll-Like Receptor 9 TLR3 Animals Immunology and Allergy MOLIMMUNO Signal Transduction |
| Zdroj: | Immunity. 31(5):737-748 |
| ISSN: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2009.09.013 |
| Popis: | SummaryIntracellular Toll-like receptor 3 (TLR3), TLR7, and TLR9 localize in endosomes and recognize single-stranded RNA and nucleotides from viruses and bacteria. This interaction induces their conformational changes resulting in the production of proinflammatory cytokines and upregulation of cell surface molecules. TLR9 requires a proteolytic cleavage for its signaling. Here, we report that myeloid and plasmacytoid dendritic cells (DCs) deficient for the asparagine endopeptidase (AEP), a cysteine lysosomal protease, showed a decrease in the secretion of proinflammatory cytokines in response to TLR9 stimulation in vitro and in vivo. Upon stimulation, full-length TLR9 was cleaved into a 72 kDa fragment and this processing was strongly reduced in DCs lacking AEP. Processed TLR9 coeluted with the adaptor molecule MyD88 and AEP after size exclusion chromatography. When expressed in AEP-deficient DCs, the 72 kDa proteolytic fragment restored TLR9 signaling. Thus, our results identify an endocytic protease playing a critical role in TLR processing and signaling in DCs. |
| Databáze: | OpenAIRE |
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