Toll-like receptors (TLR) cascades

Toll-like receptors (TLRs) are a group of highly conserved pathogen recognition receptors which initiate and regulate the immune response by controlling cytokine and chemokines expression.<p>Mammalian and avian lineages diverged from the common ancestor approximately 300 millions years ago. Although most of the genes encoding proteins of the chicken TLR cascade molecules have not been cloned and characterized directly, analyses of the chicken genome sequence has defined ten TLRs [Lynn et al. 2003, Temperley ND et al. 2008]. The avian TLR repertoire consists of single orthologs of mammalian TLRs 3, 4, 5 and 7 and distinct new chicken genes TLR15 and TLR21. The TLR2 subfamily is represented by tandemly duplicated avian TLR2 and TLR1 genes and consists of two isoforms of each gene - TLR2 type1 and 2, TLR1 type1 and 2. No functional orthologs of mammalian TLR8, TLR9 and TLR10 have been detected in the chicken genome. However, chicken heterophils and spleen cells are responsive to the broad range of mammalian TLR antagonists including ligands that stimulate mammalian TLR7/8 and TLR9 [Schwarz et al. 2007, He et al. 2006, Kogut et al. 2007].<p>TLR signaling pathways are highly conserved among vertebrates and the chicken proteins involved in the TLR signaling cascade show moderate to high identity with their human counterparts [Yilmaz et al. 2005, Temperley et al. 2008, Cormican et al. 2009]. Thus, a homology-based strategy was used to reconstruct most parts of the chicken TLR pathways in this Reactome module.<p>All TLRs share a similar structure consisting of N-terminus ectodomain with several leucine-rich regions (LRR), one or two trans-membrane domains and an intracellular C-terminus Toll/Interleukin-1 receptor domain (TIR).<p>Activation of TLR pathways occurs upon recognition and interaction with conserved motifs expressed by invading microbes, also known as pathogen-associated molecular patterns (PAMPs). Each TLR recognizes specific PAMPs.</p>Upon PAMP binding TLRs form heterodimers (TLR2 subfamily) or homodimers (all other TLRs). Activated TLRs recruit one or several TIR adaptor proteins myeloid differentiation primary response gene 88 (MyD88), TIR domain containing adaptor protein (TIRAP or MAL), TIR domain-containing adapter protein inducing IFN-beta (TRIF or TIKAM-1), and TRIF related adaptor molecule (TRAM). The fifth known adaptor SARM binds TIR as a negative competitor to TRIF.<p>All TLRs except TLR3 can initiate downstream signaling through MyD88 adaptor protein. In the MyD88-dependent pathway, once the adaptor is bound to TLR, it leads to recruitment of IL1 receptor associated kinase family IRAK, followed by activation of tumour necrosis factor receptor-associated factor 6 (TRAF6). TRAF6 is an ubiquitin E3 ligase, which in turn induces TGF-beta activating kinase 1 (TAK1) autophosphorylation. Once activated, TAK1 can ultimately mediate the induction of the transcription factor NF-kB or the mitogen-activated protein kinases (MAPK), such as JNK, p38 and ERK. This results in the translocation of the activated NF-kB and MAPKs to the nucleus and the initiation of appropriate gene transcription leading to the production of many proinflammatory cytokines and antimicrobial peptides.<p>In contrast to other TLRs, TLR3 functions only through the MyD88-independent signaling cascade, recruiting TRIF, which in turn leads to the interferon regulatory factor 3 or 7 (IRF3/7) activation. Activated IRF3 or 7 mediates innate anti-viral responses through interferon-beta expression.<p> Mammalian TLR4 can ultimately utilize both MyD88-dependent (controlled by the MyD88-TIRAP pair of adaptors) and MyD88-independent (controlled by TRAM-TRIF adaptor proteins) signaling pathways, in contrast, chicken TLR4 signaling is mediated by MyD88-TIRAP exlusively.

Toll样受体（TLRs）是一组高度保守的病原体识别受体，通过调控细胞因子和趋化因子的表达来启动和调节免疫反应。<p>哺乳动物和鸟类谱系大约在3亿年前从共同祖先分化而来。尽管编码鸡TLR级联分子蛋白的多数基因尚未直接克隆和鉴定，但对鸡基因组序列的分析已确定了十个TLRs [Lynn 等人，2003年，Temperley ND 等人，2008年]。鸟类TLR库包括哺乳动物TLR3、4、5和7的单个直系同源物，以及独特的鸡基因TLR15和TLR21。TLR2亚家族由串联复制的鸟类TLR2和TLR1基因构成，每个基因具有两种异构体——TLR2型1和2，TLR1型1和2。在鸡基因组中尚未检测到哺乳动物TLR8、TLR9和TLR10的功能直系同源物。<p>尽管如此，鸡的异嗜性白细胞和脾细胞对广泛的哺乳动物TLR拮抗剂产生反应，包括刺激哺乳动物TLR7/8和TLR9的配体 [Schwarz 等人，2007年，He 等人，2006年，Kogut 等人，2007年]。<p>TLR信号通路在脊椎动物中高度保守，参与TLR信号级联的鸡蛋白与人类同源物表现出中到高的同源性 [Yilmaz 等人，2005年，Temperley 等人，2008年，Cormican 等人，2009年]。因此，在本Reactome模块中，采用同源策略重建了鸡TLR通路的大部分部分。<p>所有TLRs均具有相似的结构，包括N端外显域，其中包含多个富含亮氨酸的区域（LRR），一个或两个跨膜结构域，以及细胞内C端Toll/白细胞介素-1受体结构域（TIR）。<p>TLR通路的激活发生在与入侵微生物表达的保守基序识别和相互作用之后，这些基序也被称为病原体相关分子模式（PAMPs）。每个TLR识别特定的PAMPs。<p>PAMP结合后，TLRs形成异源二聚体（TLR2亚家族）或同源二聚体（所有其他TLRs）。活化的TLRs募集一个或多个TIR适配蛋白，包括髓样分化初级反应基因88（MyD88）、TIR结构域含有适配蛋白（TIRAP或MAL）、TIR结构域含有适配蛋白诱导IFN-β（TRIF或TIKAM-1）和TRIF相关适配分子（TRAM）。第五个已知的适配蛋白SARM作为负竞争者与TRIF结合。<p>除了TLR3之外，所有TLRs均可通过MyD88适配蛋白启动下游信号。在MyD88依赖性途径中，适配蛋白一旦与TLR结合，就会导致IL1受体相关激酶家族IRAK的募集，随后激活肿瘤坏死因子受体相关因子6（TRAF6）。TRAF6是一种泛素E3连接酶，它反过来诱导TGF-β激活激酶1（TAK1）的自身磷酸化。一旦被激活，TAK1最终可以介导转录因子NF-kB或细胞外信号调节激酶（MAPK），如JNK、p38和ERK的诱导。这导致活化的NF-kB和MAPKs转位到细胞核，并启动适当的基因转录，从而产生许多促炎细胞因子和抗菌肽。<p>与其他TLRs不同，TLR3仅通过MyD88非依赖性信号级联发挥作用，募集TRIF，进而导致干扰素调节因子3或7（IRF3/7）的激活。活化的IRF3或7通过干扰素-β的表达介导先天抗病毒反应。<p>与TLR4利用MyD88依赖性（由MyD88-TIRAP适配器对控制）和MyD88非依赖性（由TRAM-TRIF适配蛋白控制）两种信号通路不同，鸡TLR4信号仅由MyD88-TIRAP独家介导。