Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression
Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression
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DOI：
10.1073/pnas.0611589104
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发表时间：
2007-05-01
影响因子：
11.1
通讯作者：
Gaffen, Sarah L.
中科院分区：
文献类型：
--
作者：
Maitra, Amarnath;Shen, Fang;Gaffen, Sarah L.
IL-17是一个新的促炎细胞因子家族的创始成员，该家族定义了一类新的CD 4（+）效应T细胞，称为“Th 17”。“越来越多的证据表明IL-17和Th 17细胞会导致自身免疫病理学，但人们对IL-17 RA信号传导机制知之甚少。IL-17通过其受体（IL-17 RA）激活先天性免疫细胞因子的典型基因，例如TNF α和IL-1 β，尽管它们各自的受体具有最小的序列相似性。先前的生物信息学研究预测了IL-17家族受体中与Toll/IL-1 R（TIR）结构域同源的亚结构域，称为“SEFIR结构域”。“然而，SEFIR结构域缺乏真正TIR结构域的关键基序，其功能从未得到验证。在这里，我们使用了IL-17 RA-空成纤维细胞中的重建系统来映射IL-17 RA内的功能结构域。我们证明了SEFIR结构域介导IL-17 RA信号传导独立于经典的TIR衔接子，如MyD 88和TRIF。此外，我们发现了一个以前未描述的“TIR样环”（TILL），它是NF-κ B B、MAPK激活和C/EBP β和C/EBP δ上调所必需的。TILL结构域的突变揭示了与TLR 4中的LpS（d）突变类似的位点，其使小鼠对LIPS不敏感。然而，通常在TIR结构域中发现的假定盐桥似乎是不稳定的。我们进一步鉴定了C/EBP β激活和诱导IL-17靶基因亚组所需的C-末端结构域。IL-17超家族受体的这种结构-功能分析揭示了IL-17 RA与IL-1/TLR受体相比的重要差异。
IL-17 is the founding member of a novel family of proinflammatory cytokines that defines a new class of CD4(+) effector T cells, termed "Th17." Mounting evidence suggests that IL-17 and Th17 cells cause pathology in autoimmunity, but little is known about mechanisms of IL-17RA signaling. IL-17 through its receptor (IL-17RA) activates genes typical of innate immune cytokines, such as TNF alpha and IL-1 beta, despite minimal sequence similarity in their respective receptors. A previous bioinformatics study predicted a subdomain in IL-17-family receptors with homology to a Toll/IL-1R (TIR) domain, termed the "SEFIR domain." However, the SEFIR domain lacks motifs critical for bona fide TIR domains, and its functionality was never verified. Here, we used a reconstitution system in IL-17RA-null fibroblasts to map functional domains within IL-17RA. We demonstrate that the SEFIR domain mediates IL-17RA signaling independently of classic TIR adaptors, such as MyD88 and TRIF. Moreover, we identified a previously undescribed"TIR-like loop" (TILL) required for activation of NF-kappa B, MAPK, and up-regulation of C/EBP beta and C/EBP delta. Mutagenesis of the TILL domain revealed a site analogous to the LpS(d) mutation in TLR4, which renders mice insensitive to LIPS. However, a putative salt bridge typically found in TIR domains appears to be dispensable. We further identified a C-terminal domain required for activation of C/EBP beta and induction of a subset IL-17 target genes. This structure-function analysis of a IL-17 superfamily receptor reveals important differences in IL-17RA compared with IL-1/TLR receptors.