Park, B. et al. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat. Immunol. 9, 1407-1414

Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02115, USA.
Nature Immunology (Impact Factor: 20). 11/2008; 9(12):1407-14. DOI: 10.1038/ni.1669
Source: PubMed


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.

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    • "In addition to being regulated by UNC93B1 trafficking, TLR3, 7, 8, and 9 need to be cleaved by various proteases such as cathepsins, asparagine endopeptidase, and furin-like proprotein convertases (Ewald et al., 2008, 2011; Park et al., 2008; Sepulveda et al., 2009; Garcia-Cattaneo et al., 2012; Maschalidi et al., 2012; Hipp et al., 2013). The proteolysis occurs as the TLRs are transported through acidic endosomal compartments where these enzymes are active. "
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