Li Rongpeng, Fang Lizhu, Tan Shirui, Yu Min, Li Xuefeng, He Sisi, Wei Yuquan, Li Guoping, Jiang Jianxin, Wu Min
Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND 58203-9061, USA.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China.
Cell Res. 2016 Dec;26(12):1273-1287. doi: 10.1038/cr.2016.135. Epub 2016 Nov 18.
Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems in bacteria and archaea provide adaptive immunity against invading foreign nucleic acids. Previous studies suggest that certain bacteria employ their Type II CRISPR-Cas systems to target their own genes, thus evading host immunity. However, whether other CRISPR-Cas systems have similar functions during bacterial invasion of host cells remains unknown. Here we identify a novel role for Type I CRISPR-Cas systems in evading host defenses in Pseudomonas aeruginosa strain UCBPP-PA14. The Type I CRISPR-Cas system of PA14 targets the mRNA of the bacterial quorum-sensing regulator LasR to dampen the recognition by toll-like receptor 4, thus diminishing the pro-inflammatory responses of the host in cell and mouse models. Mechanistically, this nuclease-mediated RNA degradation requires a "5'-GGN-3'" recognition motif in the target mRNA, and HD and DExD/H domains in Cas3 of the Type I CRISPR-Cas system. As LasR and Type I CRISPR-Cas systems are ubiquitously present in bacteria, our findings elucidate an important common mechanism underlying bacterial virulence.
细菌和古细菌中的成簇规律间隔短回文重复序列（CRISPR）-CRISPR相关蛋白（Cas）系统可提供针对入侵的外来核酸的适应性免疫。先前的研究表明，某些细菌利用其II型CRISPR-Cas系统靶向自身基因，从而逃避宿主免疫。然而，在细菌入侵宿主细胞过程中，其他CRISPR-Cas系统是否具有类似功能仍不清楚。在此，我们确定了I型CRISPR-Cas系统在铜绿假单胞菌菌株UCBPP-PA14逃避宿主防御中的新作用。PA14的I型CRISPR-Cas系统靶向细菌群体感应调节因子LasR的mRNA，以减弱Toll样受体4的识别，从而在细胞和小鼠模型中减少宿主的促炎反应。从机制上讲，这种核酸酶介导的RNA降解需要靶mRNA中的“5'-GGN-3'”识别基序，以及I型CRISPR-Cas系统的Cas3中的HD和DExD/H结构域。由于LasR和I型CRISPR-Cas系统在细菌中普遍存在，我们的发现阐明了细菌毒力的一个重要共同机制。
