Pivotal Advance:: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound
Pivotal Advance:: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound
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DOI：
10.1189/jlb.1206746
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发表时间：
2007-10-01
影响因子：
5.5
通讯作者：
Sette, Claudio
中科院分区：
文献类型：
--
作者：
Loiarro, Maria;Capolunghi, Federica;Sette, Claudio
MyD88是一种适配蛋白，在IL-1R和几种TLRs诱导的细胞内信号转导中起重要作用。其核心功能是其Toll/IL-1R翻译起始区(TIR)结构域能够与受体异源二聚，并与另一种MyD88分子同源二聚，从而促进下游信号分子的募集，如丝氨酸/苏氨酸激酶IL-1R相关激酶1(IRAK1)和IRAK4。在这里，我们合成了一种模拟MyD88-TIR结构域BB-环中七肽结构的合成肽模拟物(ST2825)，并检测了其活性，该结构干扰了MyD88信号转导。在免疫共沉淀实验中，ST2825抑制了MyD88的二聚化。这种效应是TIR结构域的同源二聚所特有的，并不影响死亡结构域的同源二聚。此外，ST2825干扰MyD88对IRAK1和IRAK4的募集，导致抑制IL-1β介导的核因子-kappa B转录活性的激活。灌胃给药后，ST2825剂量依赖性地抑制IL-1β诱导的IL-6的产生。最后，我们观察到ST2825抑制B细胞的增殖和向浆细胞的分化，以回应CpG诱导的TLR9的激活，TLR9是一种需要MyD88进行细胞内信号传递的受体。我们的结果表明，ST2825通过干扰MyD88的同源二聚化来阻断IL-1R/TLR信号转导，提示它可能在慢性炎症性疾病的治疗中具有潜在的作用。
MyD88 is an adaptor protein, which plays an essential role in the intracellular signaling elicited by IL-1R and several TLRs. Central to its function is the ability of its Toll/IL-1R translation initiation region (TIR) domain to heterodimerize with the receptor and to homodimerize with another MyD88 molecule to favor the recruitment of downstream signaling molecules such as the serine/threonine kinases IL-1R-associated kinase 1 (IRAK1) and IRAK4. Herein, we have synthesized and tested the activity of a synthetic peptido-mimetic compound (ST2825) modeled after the structure of a heptapeptide in the BB-loop of the MyD88-TIR domain, which interferes with MyD88 signaling. ST2825 inhibited MyD88 dimerization in coimmunoprecipitation experiments. This effect was specific for homodimerization of the TIR domains and did not affect homodimerization of the death domains. Moreover, ST2825 interfered with recruitment of IRAK1 and IRAK4 by MyD88, causing inhibition of IL-1 beta-mediated activation of NF-kappa B transcriptional activity. After oral administration, ST2825 dose-dependently inhibited IL-1 beta-induced production of IL-6 in treated mice. Finally, we observed that ST2825 suppressed B cell proliferation and differentiation into plasma cells in response to CpG-induced activation of TLR9, a receptor that requires MyD88 for intracellular signaling. Our results indicate that ST2825 blocks IL-1R/TLR signaling by interfering with MyD88 homodimerization and suggest that it may have therapeutic potential in treatment of chronic inflammatory diseases.