Toll9 from Bombyx mori functions as a pattern recognition receptor that shares features with Toll-like receptor 4 from mammals
Toll9 from Bombyx mori functions as a pattern recognition receptor that shares features with Toll-like receptor 4 from mammals
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DOI：
10.1073/pnas.2103021118
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发表时间：
2021-05
期刊：
影响因子：
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通讯作者：
Ruonan Zhang;Xiaofeng Li;Jie Zhang;Yanjun Li;Yuan Wang;Yuhang Song;Feifei Ren;Huiyu Yi;Xiaojuan Deng;Yangjin Zhong;Yang Cao;M. Strand;Xiao-qiang Yu;Wanying Yang
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文献类型：
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作者：
Ruonan Zhang;Xiaofeng Li;Jie Zhang;Yanjun Li;Yuan Wang;Yuhang Song;Feifei Ren;Huiyu Yi;Xiaojuan Deng;Yangjin Zhong;Yang Cao;M. Strand;Xiao-qiang Yu;Wanying Yang
意义Toll/Toll样受体是无脊椎动物和脊椎动物先天免疫系统的关键调节因子。然而，虽然哺乳动物的Toll样受体作为模式识别受体直接结合微生物相关的配体，但节肢动物的Toll通常被认为是由Spätzle细胞因子激活的。在这里，我们展示了家蚕Tol19作为模式识别受体的功能，它与脂多糖结合。我们的结果为昆虫Toll和哺乳动物Toll样受体家族成员之间的结构和功能保守提供了联系。Toll/Toll样受体是无脊椎动物和脊椎动物先天免疫系统的关键调节因子。然而，虽然哺乳动物的TLRs直接识别病原体相关的分子模式，但昆虫Toll途径被认为主要是通过结合Spätzle细胞因子激活的，这些细胞因子是由非活性前体处理的，以响应微生物感染。这项研究中产生的系统发育和结构数据支持早期的结果，即Tol19成员与其他昆虫Toll9成员的不同之处在于与哺乳动物的TLR4组聚在一起，TLR4组通过与髓系分化-2(MD-2)样蛋白相互作用识别脂多糖(LPS)。功能实验表明，家蚕BmToll9也通过与两个MD-2类似蛋白相互作用识别内毒素，这两个蛋白以前被命名为BmEsr16和BMPP，我们在本研究中分别称为BmMD-2A和BmMD-2B。由BmTol19胞外区和小鼠TLR4跨膜区和Toll/IL-1(TIR)结构域组成的嵌合BmToll9-TLR4受体也激活了内毒素诱导的小鼠细胞释放炎症因子，但只有在BmMD-2A或BmMD-2B存在的情况下才能激活。总之，我们的结果表明，BmToll9是一种内毒素的模式识别受体，与哺乳动物的TLR4-MD-2-内毒素途径具有保守的特征。
Significance Toll/Toll-like receptors are key regulators of the innate immune system in both invertebrates and vertebrates. However, while mammalian Toll-like receptors function as pattern recognition receptors that directly bind microbe-associated ligands, arthropod Tolls are generally thought to be activated by Spätzle cytokines. Here, we show that Toll9 from the silkmoth Bombyx mori functions as a pattern recognition receptor that binds lipopolysaccharide. Our results provide a link for both structural and functional conservation between an insect Toll and a mammalian Toll-like receptor family member. Toll/Toll-like receptors (TLRs) are key regulators of the innate immune system in both invertebrates and vertebrates. However, while mammalian TLRs directly recognize pathogen-associated molecular patterns, the insect Toll pathway is thought to be primarily activated by binding Spätzle cytokines that are processed from inactive precursors in response to microbial infection. Phylogenetic and structural data generated in this study supported earlier results showing that Toll9 members differ from other insect Tolls by clustering with the mammalian TLR4 group, which recognizes lipopolysaccharide (LPS) through interaction with myeloid differentiation-2 (MD-2)–like proteins. Functional experiments showed that BmToll9 from the silkmoth Bombyx mori also recognized LPS through interaction with two MD-2–like proteins, previously named BmEsr16 and BmPP, that we refer to in this study as BmMD-2A and BmMD-2B, respectively. A chimeric BmToll9–TLR4 receptor consisting of the BmToll9 ectodomain and mouse TLR4 transmembrane and Toll/interleukin-1 (TIR) domains also activated LPS-induced release of inflammatory factors in murine cells but only in the presence of BmMD-2A or BmMD-2B. Overall, our results indicate that BmToll9 is a pattern recognition receptor for LPS that shares conserved features with the mammalian TLR4–MD-2–LPS pathway.