Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9.
Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9.
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Toll样受体（TLR）激活先天免疫系统以响应病原体。在这里，我们表明TLR 9蛋白水解切割是TLR 9信号传导的先决条件。抑制溶酶体蛋白水解使TLR 9失活。由此产生的TLR 9的C-末端片段包括TLR 9胞外域的一部分，以及跨膜和胞质结构域。该切割片段与TLR 9配体CpG结合，并且当在Tlr 9 −/−树突细胞中表达时，恢复CpG诱导的细胞因子产生。虽然组织蛋白酶L在无细胞体外系统中产生必需的TLR 9切割产物，但几种蛋白酶影响完整细胞中的TLR 9切割。因此，溶酶体蛋白水解通过促进TLR 9的特异性切割而有助于先天免疫。
Toll-like receptors (TLRs) activate the innate immune system in response to pathogens. Here we showed that TLR9 proteolytic cleavage is a prerequisite for TLR9 signaling. Inhibition of lysosomal proteolysis rendered TLR9 inactive. The C-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, and, when expressed in Tlr9−/− dendritic cells, restored CpG-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.