A CC' loop decoy peptide blocks the interaction between Act1 and IL-17RA to attenuate IL-17- and IL-25-induced inflammation.
A CC' loop decoy peptide blocks the interaction between Act1 and IL-17RA to attenuate IL-17- and IL-25-induced inflammation.
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DOI：
10.1126/scisignal.2001843
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发表时间：
2011-11-01
影响因子：
7.3
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Liu C;Swaidani S;Qian W;Kang Z;Sun P;Han Y;Wang C;Gulen MF;Yin W;Zhang C;Fox PL;Aronica M;Hamilton TA;Misra S;Deng J;Li X
白细胞介素-17（IL-17）和IL-25信号传导诱导编码炎性因子的基因的表达，并且它们与各种炎性疾病的病理学有关。核因子κB（NF-κB）激活因子1（Act 1）是一种衔接蛋白和E3泛素连接酶，对IL-17和IL-25信号传导至关重要，并通过其SEFIR [SEF（与成纤维细胞生长因子基因相似的表达）/IL-17 R]结构域之间的异型相互作用募集至其受体。SEFIR结构域的建模已显示其与Toll样受体（TLR）和IL-1 R的Toll-IL-1受体（TIR）结构域的结构相似性。而TIR的BB′环是TIR-TIR相互作用所必需的，我们发现从Act 1或IL-17 RA（IL-17 R和IL-25 R的共同亚基）中删除BB′环并不影响Act 1-IL-17 RA相互作用。相反，从Act 1或IL-17 RA中删除CC′环消除了Act 1和IL-17 RA之间的相互作用，表明SEFIR和TIR结构域以不同的方式相互作用。表面等离子体共振测量表明，对应于CC′环的肽直接结合IL-17 RA。基于CC′环序列的细胞可渗透性诱饵肽抑制IL-17和IL-25介导的信号传导，并抑制IL-17和IL-25诱导的体外反应和体内肺部炎症。总之，这些发现为SEFIR与TIR结构域相互作用的特异性和随后的信号传导提供了分子基础。此外，我们认为SEFIR结构域的CC′环基序是一个有希望的治疗IL-17和IL-25相关炎症性疾病的靶点。
Interleukin-17 (IL-17) and IL-25 signaling induce the expression of genes that encode inflammatory factors and they are implicated in the pathology of various inflammatory diseases. Nuclear factor κB (NF-κB) activator 1 (Act1) is an adaptor protein and E3 ubiquitin ligase that is critical for IL-17 and IL-25 signaling, and it is recruited to their receptors through heterotypic interactions between their SEFIR [SEF (similar expression to fibroblast growth factor genes)/IL-17R] domains. Modeling of SEFIR domains has shown their structural similarity with the Toll-IL-1 receptor (TIR) domains of Toll-like receptors (TLRs) and the IL-1R. Whereas the BB′ loop of TIR is required for TIR-TIR interactions, we found that deletion of the BB′ loop from Act1 or IL-17RA (a common subunit of IL-17R and IL-25R) did not affect Act1–IL-17RA interactions. Instead, deletion of the CC′ loop from Act1 or IL-17RA abolished the interaction between Act1 and IL-17RA, suggesting that SEFIR and TIR domains interact in different manners. Surface plasmon resonance measurements showed that a peptide corresponding to the CC′ loop bound directly to IL-17RA. A cell-permeable decoy peptide based on the CC′ loop sequence inhibited IL-17- and IL-25-mediated signaling, and it inhibited IL-17- and IL-25-induced responses in vitro and pulmonary inflammation in vivo. Together, these findings provide the molecular basis for the specificity of SEFIR versus TIR domain interactions and consequent signaling. Moreover, we suggest that the CC′ loop motif of SEFIR domains is a promising target for therapeutic strategies against IL-17- and IL-25-asssociated inflammatory diseases.
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影响因子：
4.4
作者：
Claudio, Estefania;Sonder, Soren Ulrik;Saret, Sun;Carvalho, Gabrielle;Ramalingam, Thirumalai R.;Wynn, Thomas A.;Chariot, Alain;Garcia-Perganeda, Antonio;Leonardi, Antonio;Paun, Andrea;Chen, Amy;Ren, Nina Y.;Wang, Hongshan;Siebenlist, Ulrich
通讯作者：
Siebenlist, Ulrich
DOI：
10.4049/jimmunol.182.3.1631
发表时间：
2009-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Swaidani S;Bulek K;Kang Z;Liu C;Lu Y;Yin W;Aronica M;Li X
通讯作者：
Li X
影响因子：
30.5
作者：
Qian, Youcun;Liu, Caini;Li, Xiaoxia
通讯作者：
Li, Xiaoxia
影响因子：
14.8
作者：
通讯作者：
--
DOI：
10.1084/jem.20061401
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Schnyder-Candrian S;Togbe D;Couillin I;Mercier I;Brombacher F;Quesniaux V;Fossiez F;Ryffel B;Schnyder B
通讯作者：
Schnyder B