IFIT蛋白是人類免疫系統(tǒng)中保衛(wèi)機(jī)體的步兵,，負(fù)責(zé)檢測病毒并抵御感染。現(xiàn)在,，McGill大學(xué)和奧地利科學(xué)院分子醫(yī)學(xué)研究中心的研究人員揭示了IFIT蛋白作用的分子機(jī)制,，它們不僅識別外源病毒RNA，還揪住病毒基因組阻止其復(fù)制,，從而阻斷感染,。這項研究有望幫助人們開發(fā)新藥物來對抗多種免疫系統(tǒng)疾病。
這項研究由Bhushan Nagar教授和Dr. Giulio Superti-Furga共同領(lǐng)導(dǎo),。2011年,，研究人員意外發(fā)現(xiàn)IFIT蛋白能直接與病毒RNA相互作用，阻斷其復(fù)制,。在此基礎(chǔ)上，這項新研究進(jìn)一步揭示了IFIT區(qū)分病毒RNA與自身正常分子的機(jī)制,，展示了該蛋白只捕獲病毒RNA的能力,。這項研究于一月十三日發(fā)表在Nature雜志上。
“免疫系統(tǒng)中的守衛(wèi)蛋白一直在搜尋病原體的外源分子,，以此來檢測病毒和細(xì)菌等病原體的感染,，” Nagar教授解釋道,，“一旦檢測到了病原體，宿主細(xì)胞就會啟動快速應(yīng)答,，生成一系列防御分子來阻斷和清除感染,。IFIT蛋白就是這些防御分子中的關(guān)鍵成員。”
當(dāng)病毒進(jìn)入細(xì)胞時,，會生成末端暴露出三個磷酸基團(tuán)的RNA,，以便自我復(fù)制。而這就是病毒RNA與其宿主人類RNA的區(qū)別,。這時,，先天免疫系統(tǒng)的受體往往能夠檢測到來自病毒的外源分子，并在感染細(xì)胞及附近未感染細(xì)胞中啟動信號級聯(lián)打開抗病毒程序,。這種抗菌程序會生成幾百種不同的蛋白,，聯(lián)手對抗病毒感染。
Nagar實驗室的研究生Yazan Abbas利用X射線晶體衍射等生物物理學(xué)技術(shù),，直接捕捉到了IFIT識別外源RNA的過程,，展現(xiàn)了IFIT與RNA間的相互作用。研究人員發(fā)現(xiàn),，IFIT蛋白有一個特殊的結(jié)合區(qū)域,，只能與病毒RNA的末端相匹配。人類RNA無法與這一區(qū)域發(fā)生緊密的相互作用,，也就避免了危險的自身免疫反應(yīng),。
“一旦IFIT蛋白抓住了病毒RNA，病毒就無法對其進(jìn)行復(fù)制,，” Superti-Furga說,，“流感病毒和狂犬病毒等許多病毒都依賴三磷酸末端的RNA進(jìn)行復(fù)制，因此這一研究對于細(xì)胞抵御病毒的機(jī)制具有廣泛的啟示,。”
這項研究還將有助于開發(fā)新藥物來治療多種免疫系統(tǒng)疾病,。“我們的發(fā)現(xiàn)對于開發(fā)新藥物靶標(biāo)IFIT蛋白很有用，特別是在需要抑制免疫應(yīng)答的時候,，例如對炎癥或癌癥進(jìn)行治療,，” Nagar說。(生物谷Bioon.com)
doi:10.1038/nature11783
PMC:
PMID:
Structural basis for viral 5′-PPP-RNA recognition by human IFIT proteins
Yazan M. Abbas, Andreas Pichlmair, Maria W. Górna, Giulio Superti-Furga & Bhushan Nagar
Interferon-induced proteins with tetratricopeptide repeats (IFITs) are innate immune effector molecules that are thought to confer antiviral defence through disruption of protein–protein interactions in the host translation-initiation machinery. However, it was recently discovered that IFITs can directly recognize viral RNA bearing a 5′-triphosphate group (PPP-RNA), which is a molecular signature that distinguishes it from host RNA. Here we report crystal structures of human IFIT5, its complex with PPP-RNAs, and an amino-terminal fragment of IFIT1. The structures reveal a new helical domain that houses a positively charged cavity designed to specifically engage only single-stranded PPP-RNA, thus distinguishing it from the canonical cytosolic sensor of double-stranded viral PPP-RNA, retinoic acid-inducible gene I (RIG-I, also known as DDX58). Mutational analysis, proteolysis and gel-shift assays reveal that PPP-RNA is bound in a non-sequence-specific manner and requires a 5′-overhang of approximately three nucleotides. Abrogation of PPP-RNA binding in IFIT1 and IFIT5 was found to cause a defect in the antiviral response by human embryonic kidney cells. These results demonstrate the mechanism by which IFIT proteins selectively recognize viral RNA, and lend insight into their downstream effector function.
