天然免疫不仅是免疫系统抵抗微生物感染的第一道防线，而且影响到机体与共生微生物菌群的关系，这对维持健康起着重要作用。果蝇天然免疫同哺乳动物的天然免疫具有相当程度的相似性。果蝇天然免疫反应的重要特点是组织特异的，瞬时的调节一系列抗菌肽(AMPs)的表达。由于每种抗菌肽都有特异的抗菌谱，对每种抗菌肽在数量和维持时间上的严格调节对整体抗菌状况和维持共生微生物菌群均有重要作用。因此阐明具有不同表达动态特性和抗菌谱的AMP的不同基因表达调节非常重要，特别是在转录后水平上，通过位于mRNA 3’非翻译区(3’UTR)上的调控元件——富含AU的序列(ARE)对抗菌肽基因实现的不同表达调控尤为重要。
中科院上海生命科学院/上海交通大学医学院健康科学研究所博士研究生韦有恒等，在导师马维骏研究员的指导下，揭示了抗菌肽的表达具有不同的转录后水平调控，可以对产生动态可控的抗菌谱和抗菌活性发挥重要的作用，使得机体能达到控制感染和维持共生菌群的平衡；观察到具有不同表达动态特性和抗菌谱的抗菌肽的mRNA稳定性不同，这是由果蝇Tis11蛋白介导的，它与抗菌肽mRNA的3’UTR上的调控元件ARE作用使得mRNA变得不稳定；通过针对Tis11蛋白的免疫共沉淀实验发现，Tis11能够同CecA1 mRNA共存于复合物沉淀中，且其它被检测抗菌肽mRNA均未发生这种相互作用；进一步实验证明p38MAPK途径通过抑制Tis11介导的mRNA降解对维持含有ARE元件的mRNAs稳定性具有重要作用。研究结果表明对AMP基因表达的精确调控有着进化上保守且重要的分子基础，同时这些调控机制赋予机体产生动态可控的抗菌谱，从而使得机体天然免疫在抵抗感染与维持共生菌群中获得良好的平衡。
此研究成果发表在国际学术刊物《核酸研究》上(Nucleic Acids Research，2009年9月在线)，本项研究工作得到了国家自然科学基金的支持。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
