Dynamic control of nucleic-acid-sensing Toll-like receptors by the endosomal compartment.
Dynamic control of nucleic-acid-sensing Toll-like receptors by the endosomal compartment.
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内体区室对核酸感应 Toll 样受体的动态控制。
DOI：
10.1093/intimm/dxab037
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发表时间：
2021
影响因子：
4.4
通讯作者：
and Murakami Y.
中科院分区：
文献类型：
--
作者：
Miyake K;Saitoh S-I;Fukui R;Shibata T;Sato R;and Murakami Y.
Toll样受体（TLRs）在内质网中合成，并与分子伴侣如Unc 93 B1和与TLR 4A（PRAT 4A）-gp 96复合物相关的蛋白质一起成熟。TLR-Unc 93 B1复合物移动到内体区室，其中蛋白酶如组织蛋白酶通过TLR的细胞外结构域的蛋白水解切割来激活它们的反应性。在没有蛋白水解切割的情况下，细胞外结构域中的未切割环阻止了NA敏感TLR的配体依赖性二聚化。此外，Unc 93 B1的结合抑制TLR 3和TLR 9的配体依赖性二聚化，因此Unc 93 B1在二聚化之前从这些TLR中释放。配体激活的NA敏感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至细胞外周以产生I型干扰素。在内体区室中，DNA和RNA分别被DNA酶和RNA酶降解，产生降解产物。DNA酶2A和RNA酶T2分别产生TLR 9和TLR 8的配体。在该机制中，DNA酶和RNA酶控制对内体区室中的NA的先天免疫应答。NA敏感TLR和内体区室一起工作，通过内体监测环境线索，并决定启动先天免疫应答。
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 pro-inflammatory 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.
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