天然免疫不僅是免疫系統(tǒng)抵抗微生物感染的第一道防線，而且影響到機(jī)體與共生微生物菌群的關(guān)系,，這對維持健康起著重要作用。果蠅天然免疫同哺乳動(dòng)物的天然免疫具有相當(dāng)程度的相似性。果蠅天然免疫反應(yīng)的重要特點(diǎn)是組織特異的,，瞬時(shí)的調(diào)節(jié)一系列抗菌肽(AMPs)的表達(dá)。由于每種抗菌肽都有特異的抗菌譜,，對每種抗菌肽在數(shù)量和維持時(shí)間上的嚴(yán)格調(diào)節(jié)對整體抗菌狀況和維持共生微生物菌群均有重要作用,。因此闡明具有不同表達(dá)動(dòng)態(tài)特性和抗菌譜的AMP的不同基因表達(dá)調(diào)節(jié)非常重要，特別是在轉(zhuǎn)錄后水平上,，通過位于mRNA 3’非翻譯區(qū)(3’UTR)上的調(diào)控元件——富含AU的序列(ARE)對抗菌肽基因?qū)崿F(xiàn)的不同表達(dá)調(diào)控尤為重要,。
中科院上海生命科學(xué)院/上海交通大學(xué)醫(yī)學(xué)院健康科學(xué)研究所博士研究生韋有恒等，在導(dǎo)師馬維駿研究員的指導(dǎo)下,，揭示了抗菌肽的表達(dá)具有不同的轉(zhuǎn)錄后水平調(diào)控,，可以對產(chǎn)生動(dòng)態(tài)可控的抗菌譜和抗菌活性發(fā)揮重要的作用，使得機(jī)體能達(dá)到控制感染和維持共生菌群的平衡,；觀察到具有不同表達(dá)動(dòng)態(tài)特性和抗菌譜的抗菌肽的mRNA穩(wěn)定性不同,，這是由果蠅Tis11蛋白介導(dǎo)的，它與抗菌肽mRNA的3’UTR上的調(diào)控元件ARE作用使得mRNA變得不穩(wěn)定,；通過針對Tis11蛋白的免疫共沉淀實(shí)驗(yàn)發(fā)現(xiàn),，Tis11能夠同CecA1 mRNA共存于復(fù)合物沉淀中,，且其它被檢測抗菌肽mRNA均未發(fā)生這種相互作用；進(jìn)一步實(shí)驗(yàn)證明p38MAPK途徑通過抑制Tis11介導(dǎo)的mRNA降解對維持含有ARE元件的mRNAs穩(wěn)定性具有重要作用,。研究結(jié)果表明對AMP基因表達(dá)的精確調(diào)控有著進(jìn)化上保守且重要的分子基礎(chǔ),，同時(shí)這些調(diào)控機(jī)制賦予機(jī)體產(chǎn)生動(dòng)態(tài)可控的抗菌譜，從而使得機(jī)體天然免疫在抵抗感染與維持共生菌群中獲得良好的平衡,。
此研究成果發(fā)表在國際學(xué)術(shù)刊物《核酸研究》上(Nucleic Acids Research,，2009年9月在線)，本項(xiàng)研究工作得到了國家自然科學(xué)基金的支持,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nucleic Acids Research, doi:10.1093/nar/gkp693
Differential regulation of mRNA stability controls the transient expression of genes encoding Drosophila antimicrobial peptide with distinct immune response characteristics
Youheng Wei1,2, Qianghai Xiao1,2, Ting Zhang1, Zongchun Mou1,2, Jia You1,2 and Wei-Jun Ma1,*
1Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), 225 South Chongqing Road, Shanghai 200025 and 2Graduate School of the Chinese Academy of Sciences, China
The tight regulation of transiently expressed antimicrobial peptides (AMPs) with a distinct antimicrobial spectrum and different expression kinetics contributes greatly to the properly regulated immune response for resistance to pathogens and for the maintenance of mutualistic microbiota in Drosophila. The important role of differential regulation of AMP expression at the posttranscriptional level needs to be elucidated. It was observed that the highly expressed Cecropin A1 (CecA1) mRNA encoding a broad antimicrobial spectrum AMP against both bacteria and fungi decayed more quickly than did the moderately expressed Diptericin mRNA encoding AMP against Gram negative bacteria. The mRNA stability of AMPs is differentially regulated and is attributed to the specific interaction between cis-acting ARE in 3'-UTR of AMP mRNA and the RNA destabilizing protein transactor Tis11 as shown in co-immunoprecipitation of the Tis11 RNP complex with CecA1 mRNA but not other AMP mRNA. The p38MAPK was further demonstrated to play a crucial role in stabilizing ARE-bearing mRNAs by inhibiting Tis11-mediated degradation in LPS induced AMP expression. This evidence suggests an evolutionarily conserved and functionally important molecular basis for and effective approach to exact control of AMP gene expression. These mechanisms thereby orchestrate a well balanced and dynamic antimicrobial spectrum of innate immunity to resist infection and maintain resident microbiota properly.
