Comprehensive analysis of the HEPN superfamily: identification of novel roles in intra-genomic conflicts, defense, pathogenesis and RNA processing.
Comprehensive analysis of the HEPN superfamily: identification of novel roles in intra-genomic conflicts, defense, pathogenesis and RNA processing.
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DOI：
10.1186/1745-6150-8-15
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发表时间：
2013-06-15
期刊：
影响因子：
5.5
通讯作者：
Aravind L
中科院分区：
文献类型：
--
作者：
Anantharaman V;Makarova KS;Burroughs AM;Koonin EV;Aravind L
以核酸为目标的酶毒素在各级生物冲突中的主要作用越来越明显，这在很大程度上要归功于比较基因组学的进步。通常，毒素迅速进化，阻碍了通过序列分析对这些蛋白质的鉴定。在这里，我们分析了一个出乎意料的广泛的毒素结构域的超家族，其中大部分具有RNA酶活性。HEPN超家族由所有α-螺旋结构域组成，这些结构域首先被鉴定为与原核生物和动物Sacsin蛋白中的DNA聚合酶β-型核苷酸转移酶相关。使用敏感的序列和结构比较方法，我们通过鉴定许多新的家族和检测几个已知蛋白质家族中的分歧的HEPN结构域，极大地扩展了HEPN超家族。新的HEPN家族包括RNase LS和LsoA催化结构域、KEN结构域（例如RNaseL和Ire 1）以及RloC和PrrC的RNase结构域。大多数HEPN结构域含有保守的基序，构成金属非依赖性内切RNA酶活性位点。一些缺乏该基序的HEPN结构域可能作为非催化性RNA结合结构域起作用，例如在甘露醇阻遏物MtlR的情况下。我们的分析表明，HEPN结构域作为毒素发挥作用，这些毒素被涉及细胞生命三个结构域的基因组内、基因组间和生物体内冲突的许多系统所共享。在原核生物中，HEPN结构域是许多毒素-抗毒素（TA）和流产感染（Abi）系统的必需组分，此外与许多限制性修饰（R-M）和CRISPR-Cas系统紧密相关，偶尔与其他防御系统如Pgl和Ter紧密相关。我们提出了HEPN结构域在这些系统中的多种作用模式的证据，其中包括与其他RNA酶结构域（例如新型RNA酶H折叠结构域，NamA）结合对病毒RNA（例如LsoA和RNA酶LS）的直接攻击，对自身RNA的自杀性或休眠诱导攻击（RM系统和可能的CRISPR-Cas系统），以及与噬菌体组分直接相互作用偶联的自杀性攻击（Abi系统）。这些研究结果是兼容的假设耦合的病原体靶向（免疫）和自我导向（程序性细胞死亡和休眠诱导）的反应，在强大的抗病毒策略的演变。我们认为，由HEPN结构域和其他功能相似的RNA酶介导的利他性细胞自杀对于亲属和群体选择以及细胞合作的进化至关重要。HEPN结构域被真核生物反复获得并整合到几个核心功能中，例如5.8S-25 S/28 S rRNA前体（Las 1）的核酸内切加工，一种新的ER膜相关RNA降解系统（C6 orf 70），在核周边（Swt 1）感应未加工的转录物。多条证据表明，与原核生物相似，HEPN蛋白在几组真核生物中被招募到抗病毒、抗转座子、凋亡系统或对未折叠蛋白（Sacsin和KEN结构域）的RNA水平应答中。广泛的序列和结构比较揭示了出乎意料的广泛存在的HEPN结构域在一个巨大的各种各样的防御和应激反应系统在整个生命之树。此外，HEPN结构域已被募集以执行基本功能，特别是在真核rRNA加工中。这些发现有望刺激实验，从而揭示生命三个领域的不同细胞过程。本文由Martijn Huynen，Igor Zhulin和Nick Grishin审阅
The major role of enzymatic toxins that target nucleic acids in biological conflicts at all levels has become increasingly apparent thanks in large part to the advances of comparative genomics. Typically, toxins evolve rapidly hampering the identification of these proteins by sequence analysis. Here we analyze an unexpectedly widespread superfamily of toxin domains most of which possess RNase activity. The HEPN superfamily is comprised of all α-helical domains that were first identified as being associated with DNA polymerase β-type nucleotidyltransferases in prokaryotes and animal Sacsin proteins. Using sensitive sequence and structure comparison methods, we vastly extend the HEPN superfamily by identifying numerous novel families and by detecting diverged HEPN domains in several known protein families. The new HEPN families include the RNase LS and LsoA catalytic domains, KEN domains (e.g. RNaseL and Ire1) and the RNase domains of RloC and PrrC. The majority of HEPN domains contain conserved motifs that constitute a metal-independent endoRNase active site. Some HEPN domains lacking this motif probably function as non-catalytic RNA-binding domains, such as in the case of the mannitol repressor MtlR. Our analysis shows that HEPN domains function as toxins that are shared by numerous systems implicated in intra-genomic, inter-genomic and intra-organismal conflicts across the three domains of cellular life. In prokaryotes HEPN domains are essential components of numerous toxin-antitoxin (TA) and abortive infection (Abi) systems and in addition are tightly associated with many restriction-modification (R-M) and CRISPR-Cas systems, and occasionally with other defense systems such as Pgl and Ter. We present evidence of multiple modes of action of HEPN domains in these systems, which include direct attack on viral RNAs (e.g. LsoA and RNase LS) in conjunction with other RNase domains (e.g. a novel RNase H fold domain, NamA), suicidal or dormancy-inducing attack on self RNAs (RM systems and possibly CRISPR-Cas systems), and suicidal attack coupled with direct interaction with phage components (Abi systems). These findings are compatible with the hypothesis on coupling of pathogen-targeting (immunity) and self-directed (programmed cell death and dormancy induction) responses in the evolution of robust antiviral strategies. We propose that altruistic cell suicide mediated by HEPN domains and other functionally similar RNases was essential for the evolution of kin and group selection and cell cooperation. HEPN domains were repeatedly acquired by eukaryotes and incorporated into several core functions such as endonucleolytic processing of the 5.8S-25S/28S rRNA precursor (Las1), a novel ER membrane-associated RNA degradation system (C6orf70), sensing of unprocessed transcripts at the nuclear periphery (Swt1). Multiple lines of evidence suggest that, similar to prokaryotes, HEPN proteins were recruited to antiviral, antitransposon, apoptotic systems or RNA-level response to unfolded proteins (Sacsin and KEN domains) in several groups of eukaryotes. Extensive sequence and structure comparisons reveal unexpectedly broad presence of the HEPN domain in an enormous variety of defense and stress response systems across the tree of life. In addition, HEPN domains have been recruited to perform essential functions, in particular in eukaryotic rRNA processing. These findings are expected to stimulate experiments that could shed light on diverse cellular processes across the three domains of life. This article was reviewed by Martijn Huynen, Igor Zhulin and Nick Grishin
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影响因子：
3.2
作者：
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作者：
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