Broad Targeting Specificity during Bacterial Type III CRISPR-Cas Immunity Constrains Viral Escape.
Broad Targeting Specificity during Bacterial Type III CRISPR-Cas Immunity Constrains Viral Escape.
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DOI：
10.1016/j.chom.2017.07.016
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发表时间：
2017-09-13
影响因子：
30.3
通讯作者：
Marraffini LA
中科院分区：
文献类型：
--
作者：
Pyenson NC;Gayvert K;Varble A;Elemento O;Marraffini LA
CRISPR基因座是由源自原核病毒和质粒的短“间隔区”序列分隔的重复序列簇，其决定宿主针对其入侵者的CRISPR-Cas免疫应答的靶标。对于I型和II型CRISPR-Cas系统，靶序列的种子或前间区序列邻近基序（PAM）中的单核苷酸突变引起免疫失败并允许病毒逃逸。这通过获得靶向相同入侵者的多个间隔区来克服。在这里，我们表明表皮葡萄球菌III-A型CRISPR-Cas系统的靶向不需要PAM或种子序列，从而防止病毒通过单核苷酸取代逃逸。相反，病毒逃逸者只能通过完全靶点缺失而产生。我们的工作表明，与I型和II型系统相反，III型CRISPR-Cas靶向的宽松特异性提供了强大的免疫应答，可以通过靶向必需噬菌体序列的单个间隔区导致病毒灭绝。在探索III-A型CRISPR-Cas系统的靶特异性时，Pyenson等人发现靶区域中的大多数点突变仍然允许强大的免疫力。因此，病毒逃避III-A型CRISPR-Cas免疫应答需要完全删除靶标，这是非常罕见的事件
CRISPR loci are a cluster of repeats separated by short “spacer” sequences derived from prokaryotic viruses and plasmids that determine the targets of the host’s CRISPR-Cas immune response against its invaders. For type I and II CRISPR-Cas systems, single-nucleotide mutations in the seed or protospacer adjacent motif (PAM) of the target sequence cause immune failure and allow viral escape. This is overcome by the acquisition of multiple spacers that target the same invader. Here we show that targeting by the Staphylococcus epidermidis type III-A CRISPR-Cas system does not require PAM or seed sequences, and thus prevents viral escape via single-nucleotide substitutions. Instead, viral escapers can only arise through complete target deletion. Our work shows that, as opposed to type I and II systems, the relaxed specificity of type III CRISPR-Cas targeting provides robust immune responses that can lead to viral extinction with a single spacer targeting an essential phage sequence. Exploring the target specificity of type III-A CRISPR-Cas systems, Pyenson et al. find that most point mutations in the target region still allow robust immunity. As a consequence, viral escape from the type III-A CRISPR-Cas immune response requires the full deletion of the target, which is a very rare event
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