Toll-like Receptors of the Ascidian Ciona intestinalis PROTOTYPES WITH HYBRID FUNCTIONALITIES OF VERTEBRATE TOLL-LIKE RECEPTORS
Toll-like Receptors of the Ascidian Ciona intestinalis PROTOTYPES WITH HYBRID FUNCTIONALITIES OF VERTEBRATE TOLL-LIKE RECEPTORS
复制标题
DOI：
10.1074/jbc.m109.032433
复制
发表时间：
2009-10-02
影响因子：
4.8
通讯作者：
Satake, Honoo
中科院分区：
文献类型：
--
作者：
Sasaki, Naoko;Ogasawara, Michio;Satake, Honoo
固有免疫系统中的关键跨膜蛋白toll样受体（TLRs）已被认为存在于包括无脊椎动物在内的非哺乳动物生物体的基因组中。然而，真正的无脊椎动物tlr既没有结构上的研究也没有功能上的研究。在本文中，我们首先介绍了海鞘中所有tlr的结构、定位、配体识别、活性和炎症细胞因子的产生，这些tlr被命名为Ci-TLR1和Ci-TLR2。发现Ci-TLR1和Ci-TLR2氨基酸序列具有独特的结构组织，与功能表征的脊椎动物tlr序列具有适度的相似性。Ci-tlr1和ci-tlr2基因主要在胃、肠和血细胞中表达。与脊椎动物的tlr不同，HEK293细胞中表达的Ci-TLR1和Ci-TLR2定位于质膜和核内体。有趣的是，Ci-TLR1和Ci-TLR2都能刺激NF-kappa B对多种致病配体（如双链RNA）和细菌细胞壁成分的诱导，这些配体被各自的脊椎动物tlr不同地识别，这表明ci - tlr比脊椎动物tlr识别更广泛的病原体相关分子模式。刺激ci - tlr的致病性配体也在表达ci - tlr的肠和胃中诱导了Ci-TNF α的表达。这些结果证明了tlr触发的先天免疫系统在海鞘中基本上是保守的，并且与脊椎动物的tlr相比，ci - tlr具有“混合”的生物学和免疫学功能。此外，我们推测脊索动物的TLR祖先也获得了ci -TLR样的多细胞定位和病原体相关的分子模式识别。
Key transmembrane proteins in the innate immune system, Toll-like receptors (TLRs), have been suggested to occur in the genome of non-mammalian organisms including invertebrates. However, authentic invertebrate TLRs have been neither structurally nor functionally investigated. In this paper, we originally present the structures, localization, ligand recognition, activities, and inflammatory cytokine production of all TLRs of the ascidian Ciona intestinalis, designated as Ci-TLR1 and Ci-TLR2. The amino acid sequence of Ci-TLR1 and Ci-TLR2 were found to possess unique structural organization with moderate sequence similarity to functionally characterized vertebrate TLRs. ci-tlr1 and ci-tlr2 genes were expressed predominantly in the stomach and intestine as well as in hemocytes. Ci-TLR1 and Ci-TLR2 expressed in HEK293 cells, unlike vertebrate TLRs, were localized to both the plasma membrane and endosomes. Intriguingly, both Ci-TLR1 and Ci-TLR2 stimulate NF-kappa B induction in response to multiple pathogenic ligands such as double-stranded RNA, and bacterial cell wall components that are differentially recognized by respective vertebrate TLRs, revealing that Ci-TLRs recognize broader pathogen-associated molecular patterns than vertebrate TLRs. The Ci-TLR-stimulating pathogenic ligands also induced the expression of Ci-TNF alpha in the intestine and stomach where Ci-TLRs are expressed. These results provide evidence that the TLR-triggered innate immune systems are essentially conserved in ascidians, and that Ci-TLRs possess "hybrid" biological and immunological functions, compared with vertebrate TLRs. Moreover, it is presumed that chordate TLR ancestors also acquired the Ci-TLR-like multiple cellular localization and pathogen-associated molecular pattern recognition.