Nucleic acid (NA)-sensing Toll-like receptors (TLRs) are synthesized in the endoplasmic reticulum and mature with chaperones, such as Unc93B1 and the protein associated with TLR4 A (PRAT4A)–gp96 complex. The TLR–Unc93B1 complexes move to the endosomal compartment, where proteases such as cathepsins activate their responsiveness through proteolytic cleavage of the extracellular domain of TLRs. Without proteolytic cleavage, ligand-dependent dimerization of NA-sensing TLRs is prevented by the uncleaved loop in the extracellular domains. Additionally, the association of Unc93B1 inhibits ligand-dependent dimerization of TLR3 and TLR9 and, therefore, Unc93B1 is released from these TLRs before dimerization. Ligand-activated NA-sensing TLRs induce the production of proinflammatory cytokines and act on the endosomal compartment to initiate anterograde trafficking to the cell periphery for type I interferon production. In the endosomal compartment, DNA and RNA are degraded by DNases and RNases, respectively, generating degradation products. DNase 2A and RNase T2 generate ligands for TLR9 and TLR8, respectively. In this mechanism, DNases and RNases control innate immune responses to NAs in endosomal compartments. NA-sensing TLRs and the endosomal compartment work together to monitor environmental cues through endosomes and decide to launch innate immune responses.

中文翻译：

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内体区室对核酸敏感 Toll 样受体的动态控制

核酸 (NA) 感应 Toll 样受体 (TLR) 在内质网中合成，并与伴侣蛋白如 Unc93B1 和与 TLR4 A (PRAT4A)-gp96 复合物相关的蛋白质一起成熟。TLR-Unc93B1 复合物移动到内体区室，组织蛋白酶等蛋白酶通过 TLR 胞外结构域的蛋白水解切割激活它们的反应性。在没有蛋白水解切割的情况下，细胞外结构域中未切割的环阻止了 NA 感应 TLR 的配体依赖性二聚化。此外，Unc93B1 的结合抑制 TLR3 和 TLR9 的配体依赖性二聚化，因此，Unc93B1 在二聚化之前从这些 TLR 中释放。配体激活的 NA 感应 TLR 诱导促炎细胞因子的产生并作用于内体区室以启动顺行运输到细胞外周以产生 I 型干扰素。在内涵体区室中，DNA 和 RNA 分别被 DNase 和 RNase 降解，产生降解产物。DNase 2A 和 RNase T2 分别为 TLR9 和 TLR8 生成配体。在这种机制中，DNase 和 RNase 控制内体隔室中对 NAs 的先天免疫反应。NA 感应 TLR 和内体隔室协同工作，通过内体监测环境线索，并决定启动先天免疫反应。DNase 2A 和 RNase T2 分别为 TLR9 和 TLR8 生成配体。在这种机制中，DNase 和 RNase 控制内体隔室中对 NAs 的先天免疫反应。NA 感应 TLR 和内体隔室协同工作，通过内体监测环境线索，并决定启动先天免疫反应。DNase 2A 和 RNase T2 分别为 TLR9 和 TLR8 生成配体。在这种机制中，DNase 和 RNase 控制内体隔室中对 NAs 的先天免疫反应。NA 感应 TLR 和内体隔室协同工作，通过内体监测环境线索，并决定启动先天免疫反应。