Self versus non-self discrimination during CRISPR RNA-directed immunity.
Self versus non-self discrimination during CRISPR RNA-directed immunity.
复制标题
作者：
所有免疫系统都必须区分自身和非自身，以便在不引发自身免疫的情况下击退入侵者。成簇的、规律间隔的短回文重复序列（CRISPR）位点通过一种遗传干扰途径保护细菌和古菌免受噬菌体和质粒DNA的入侵。CRISPR位点分别存在于约40%和约90%已测序的细菌和古菌基因组中，并且进化迅速，会获得新的间隔序列以适应高度动态变化的病毒群体。免疫需要入侵DNA与位于CRISPR重复序列之间的间隔序列相匹配。每个簇在基因上都与一部分cas（CRISPR相关）基因相连，这些基因共同编码40多个参与适应和干扰过程的蛋白质家族。CRISPR位点编码小的CRISPR RNA（crRNA），其包含一个完整的间隔序列，两侧是部分重复序列。crRNA间隔序列被认为是通过与入侵的“原型间隔序列”DNA直接进行沃森 - 克里克配对来识别目标的，但它们如何避免靶向编码CRISPR位点自身内部的间隔序列DNA尚不清楚。在此我们明确了CRISPR自身/非自身区分的机制。在表皮葡萄球菌中，间隔序列之外特定位置的目标/crRNA错配使外来DNA能够被干扰，而crRNA与CRISPR DNA重复序列之间的延伸配对可防止自身免疫。因此，这种CRISPR系统不仅利用crRNA的碱基配对能力来确定目标，还能使细菌染色体免受干扰。间隔序列之外的差异互补性是所有CRISPR系统的一个固有特征，这表明这种机制是解决所有免疫途径都面临的自身/非自身困境的一种广泛适用的方法。
All immune systems must distinguish self from non-self to repel invaders without inducing autoimmunity. Clustered, regularly interspaced, short palindromic repeat (CRISPR) loci protect bacteria and archaea from invasion by phage and plasmid DNA through a genetic interference pathway. CRISPR loci are present in ~ 40% and ~90% of sequenced bacterial and archaeal genomes respectively and evolve rapidly, acquiring new spacer sequences to adapt to highly dynamic viral populations. Immunity requires a sequence match between the invasive DNA and the spacers that lie between CRISPR repeats. Each cluster is genetically linked to a subset of the cas (CRISPR-associated) genes that collectively encode >40 families of proteins involved in adaptation and interference. CRISPR loci encode small CRISPR RNAs (crRNAs) that contain a full spacer flanked by partial repeat sequences. CrRNA spacers are thought to identify targets by direct Watson-Crick pairing with invasive “protospacer” DNA, but how they avoid targeting the spacer DNA within the encoding CRISPR locus itself is unknown. Here we have defined the mechanism of CRISPR self/non-self discrimination. In Staphylococcus epidermidis, target/crRNA mismatches at specific positions outside of the spacer sequence license foreign DNA for interference, whereas extended pairing between crRNA and CRISPR DNA repeats prevents autoimmunity. Hence, this CRISPR system uses the base-pairing potential of crRNAs not only to specify a target but also to spare the bacterial chromosome from interference. Differential complementarity outside of the spacer sequence is a built-in feature of all CRISPR systems, suggesting that this mechanism is a broadly applicable solution to the self/non-self dilemma that confronts all immune pathways.
登录
查看更多内容
DOI：
10.1126/science.1165771
发表时间：
2008-12-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Marraffini LA;Sontheimer EJ
通讯作者：
Sontheimer EJ
影响因子：
2.8
作者：
Pourcel, C;Salvignol, G;Vergnaud, G
通讯作者：
Vergnaud, G
影响因子：
3.2
作者：
Deveau, Helene;Barrangou, Rodolphe;Moineau, Sylvain
通讯作者：
Moineau, Sylvain
影响因子：
4.5
作者：
Hale, Caryn;Kleppe, Kyle;Terns, Michael P.
通讯作者：
Terns, Michael P.
影响因子：
64.5
作者：
SCHNEEWIND, O;MODEL, P;FISCHETTI, VA
通讯作者：
FISCHETTI, VA