2012年8月17日 訊 /生物谷BIOON/ --身體對(duì)入侵的細(xì)菌或病毒產(chǎn)生的初始反應(yīng)是由先天免疫系統(tǒng)調(diào)控著的,，在這種免疫系統(tǒng)中,，細(xì)胞分泌出被稱(chēng)作細(xì)胞因子的信號(hào)分子從而促進(jìn)炎癥產(chǎn)生和對(duì)被身體識(shí)別為外來(lái)物質(zhì)的靶標(biāo)發(fā)動(dòng)一般性反擊,。比如，蛋白Toll樣受體3(Toll-like receptor 3, TLR3)有助于啟動(dòng)對(duì)抗病毒的先天免疫反應(yīng),。
如今,，來(lái)自新加坡科技研究局(A*STAR)下屬的生物處理科技研究院的Kong-Peng Lam和同事們證實(shí)TLR3識(shí)別病毒遺傳物質(zhì)，隨后通過(guò)磷酸化過(guò)程而發(fā)生激活。
研究人員鑒定出Bruton酪氨酸激酶(Bruton’s tyrosine kinase, BTK)為這種途徑的TLR3激活酶(TLR3-activating enzym),?；贐TK在免疫功能中的顯著性作用：編碼它的基因發(fā)生突變會(huì)導(dǎo)致X-連鎖無(wú)丙種球蛋白血癥(X-linked agammaglobulinemia)產(chǎn)生，他們發(fā)現(xiàn)BTK是一種大有希望的候選物,。這種疾病的特征在于B細(xì)胞產(chǎn)生和功能存在故障,。Lam說(shuō)，“這些病人也對(duì)復(fù)發(fā)的細(xì)菌和病毒感染非常敏感,，這就提示著B(niǎo)TK可能參與先天性免疫反應(yīng),。”
為了驗(yàn)證他們的假設(shè)，研究人員給小鼠注射多聚胞苷酸(polyribocytidylic acid)---這種分子類(lèi)似病毒RNA,，能夠觸發(fā)抗病毒免疫反應(yīng),。在這種小鼠中，這種處理能夠觸發(fā)一種強(qiáng)烈的能夠?qū)е聰⊙孕菘水a(chǎn)生的炎性過(guò)度反應(yīng),。然而,，經(jīng)證實(shí)BTK缺失的小鼠和TLR3缺失的小鼠抵抗敗血性休克，這提示著這兩種分子在同一個(gè)途徑中相互協(xié)作,。TLR3激活也產(chǎn)生促進(jìn)被稱(chēng)作干擾素β(interferon β, IFN-β)的免疫刺激性分子產(chǎn)生的信號(hào),，然而，在小鼠中,，BTK缺失有效地破壞這種反應(yīng),。相應(yīng)地，BTK缺失的小鼠也要比野生型小鼠更不能夠?qū)⒌歉餆岵《緩捏w內(nèi)清除出去,。
生化實(shí)驗(yàn)清晰地證實(shí)BTK是TLR3磷酸化所必需的,。在激活之后，TLR3結(jié)合到TRIF上,，其中TRIF允許它與多種其他的信號(hào)分子相互作用,。然而，沒(méi)有BTK,，TLR3不能經(jīng)歷磷酸化,。因此，TRIF不能結(jié)合到下游信號(hào)分子,，因而阻止信號(hào)級(jí)聯(lián)反應(yīng)產(chǎn)生。
這項(xiàng)研究提示著靶向BTK的藥物可能能夠作為一種有用的免疫調(diào)節(jié)工具,。(生物谷Bioon.com)
本文編譯自A single enzyme plays a critical role in helping the body effectively fight viral infection
doi: 10.1073/pnas.1119238109
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PMID:
Bruton’s tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response
Koon-Guan Leea, Shengli Xua, Zi-Han Kanga, Jianxin Huoa, Mei Huangb, Dingxiang Liub, Osamu Takeuchic, Shizuo Akirac, and Kong-Peng Lam
Toll-like receptor 3 (TLR3) mediates antiviral response by recognizing double-stranded RNA. Its cytoplasmic domain is tyrosine phosphorylated upon ligand binding and initiates downstream signaling via the adapter TIR-containing adaptor inducing interferon–β (TRIF). However, the kinase responsible for TLR3 phosphorylation remains unknown. We show here that Bruton's tyrosine kinase (BTK)-deficient macrophages failed to secrete inflammatory cytokines and IFN-β upon TLR3 stimulation and were impaired in clearing intracellular dengue virus infection. Mutant mice were also less susceptible to D-galactosamine/p(I:C)-induced sepsis. In the absence of BTK, TLR3-induced phosphoinositide 3-kinase (PI3K), AKT and MAPK signaling and activation of NFκB, IRF3, and AP-1 transcription factors were all defective. We demonstrate that BTK directly phosphorylates TLR3 and in particular the critical Tyr759 residue. BTK point mutations that abrogate or led to constitutive kinase activity have opposite effects on TLR3 phosphorylation. Loss of BTK also compromises the formation of the downstream TRIF/receptor-interacting protein 1 (RIP1)/TBK1 complex. Thus, BTK plays a critical role in initiating TLR3 signaling.
