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首页> 外文期刊>International Immunology >A single base mutation in the PRAT4A gene reveals differential interaction of PRAT4A with Toll-like receptors
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A single base mutation in the PRAT4A gene reveals differential interaction of PRAT4A with Toll-like receptors

机译：PRAT4A基因中的一个单碱基突变揭示了PRAT4A与Toll样受体的差异相互作用

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Toll-like receptors (TLRs) play an essential role in defense responses. Immune cells express multiple TLRs which are simultaneously activated by microbial pathogens. PRotein Associated with Tlr4 A (PRAT4A) is a chaperone-like endoplasmic reticulum (ER)-resident protein required for the proper subcellular distribution of multiple TLRs. PRAT4A?/? mice show impaired expression of TLR2/4 on the cell surface and the lack of ligand-induced TLR9 relocation from the ER to endolysosome. Consequently, TLR responses to whole bacteria as well as to TLR2, 4 and 9 ligands are impaired. We here compare the interaction of these TLRs with PRAT4A. Association of endogenous PRAT4A was easily detected only with TLR4. The TLR4 region responsible for strong interaction with PRAT4A is very close to the site necessary for interaction with MD-2. By using transient expression, we were able to detect PRAT4A interaction with TLR2 and TLR9. The PRAT4A single-nucleotide mutant replacing methionine 145 with lysine (M145K) associates with TLR9 but does not rescue ligand-dependent TLR9 trafficking. By contrast, the M145K mutant weakly, if at all, associates with TLR2 and TLR4. The M145K mutant appreciably rescues cell-surface TLR2 expression and its responses in PRAT4A?/? bone marrow-derived dendritic cells, whereas little if any rescue of cell-surface TLR4/MD-2 expression and its responses occurs. These results demonstrate that PRAT4A differentially interacts with each TLR and suggest that a single-nucleotide change in the PRAT4A gene influences not only the strength of TLR responses but can also alter the relative activity of each TLR.
机译：Toll样受体（TLR）在防御反应中起重要作用。免疫细胞表达多种TLR，这些TLR同时被微生物病原体激活。与Tlr4A相关的PRotein（PRAT4A）是分子伴侣样内质网（ER）驻留蛋白，是多个TLR正确亚细胞分布所必需的。 PRAT4A ？/？小鼠在细胞表面显示TLR2 / 4的表达受损，并且缺乏配体诱导的TLR9从ER迁移至溶酶体。因此，削弱了对整个细菌以及对TLR2、4和9配体的TLR反应。我们在这里比较了这些TLR与PRAT4A的相互作用。仅使用TLR4即可轻松检测到内源性PRAT4A的关联。负责与PRAT4A发生强烈相互作用的TLR4区非常靠近与MD-2相互作用所必需的位点。通过使用瞬时表达，我们能够检测PRAT4A与TLR2和TLR9的相互作用。 PRAT4A单核苷酸突变体用赖氨酸（M145K）取代甲硫氨酸145与TLR9缔合，但不能挽救依赖配体的TLR9贩运。相比之下，M145K突变体与TLR2和TLR4几乎没有关联。 M145K突变体可在PRAT4A ？/？骨髓源性树突状细胞中挽救细胞表面TLR2表达及其应答，而挽救挽救细胞表面TLR4 / MD-2表达及其应答的可能性很小。发生。这些结果表明，PRAT4A与每个TLR差异相互作用，并表明PRAT4A基因中的单核苷酸变化不仅影响TLR反应的强度，而且还可以改变每个TLR的相对活性。

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