Pyrin- and CARD-only Proteins as Regulators of NLR Functions.
Pyrin- and CARD-only Proteins as Regulators of NLR Functions.
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DOI：
10.3389/fimmu.2013.00275
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发表时间：
2013-09-17
影响因子：
7.3
通讯作者：
Harton JA
中科院分区：
文献类型：
--
作者：
Le HT;Harton JA
激活后，Nod-like受体（NLR）组装成多蛋白复合物，如NODosome和炎性小体。该过程依赖于结构相关的Pyrin和半胱天冬酶募集（CARD）结构域与衔接蛋白（例如ASC）或效应蛋白（例如半胱天冬酶-1）之间的同域相互作用。尽管已经沿着描述了多种NLRP和NLRC复合物及其活化刺激物和相关蛋白，但较少熟悉的是限制NLR复合物组装和/或促进NLR复合物解离的过程。考虑到限制有害的慢性炎症的重要性，这种调节机制是重要的，并且可能很多。由单独的Pyrin结构域（Pyrin-only）或CARD结构域（CARD-only）组成的蛋白质具有明显的作为NLR复合物的竞争性抑制剂的潜在能力。事实上，仅Pyrin-only蛋白（POP）和仅CARD蛋白（COP）都被描述为半胱天冬酶-1和/或NLR-炎性小体激活的调节剂，并且不令人惊讶地被描述为介导发病机制的因子。虽然目前明确的病原体编码的持久性有机污染物的例子仅限于痘病毒科的成员，人类基因组可能编码三种持久性有机污染物（POP 1，POP 2和潜在的POP 3），其中只有POP 2是已知的，以防止NLR：ASC的相互作用，和三个COP（COP/伪ICE，印加，和ICEBERG），最初描述的能力，抑制半胱天冬酶-1活性。令人惊讶的是，在真核生物物种中，持久性有机污染物和COP似乎是最近进化的，仅限于高等灵长类动物，这表明强大的选择压力推动了它们的出现。尽管了解NLR功能调控的重要性，相对较少的注意力已经致力于揭示这些有趣的蛋白质的生物学影响。这篇综述强调了我们对持久性有机污染物和COP的理解的现状，关注蛋白质的相互作用、功能、进化、对健康和疾病的影响以及悬而未决的问题。
Upon activation Nod-like receptors (NLRs) assemble into multi-protein complexes such as the NODosome and inflammasome. This process relies upon homo domain interactions between the structurally related Pyrin and caspase-recruitment (CARD) domains and adaptor proteins, such as ASC, or effector proteins, such as caspase-1. Although a variety of NLRP and NLRC complexes have been described along with their activating stimuli and associated proteins, less familiar are processes limiting assembly and/or promoting dissociation of NLR complexes. Given the importance of limiting harmful, chronic inflammation, such regulatory mechanisms are significant and likely numerous. Proteins comprised of a solitary Pyrin domain (Pyrin-only) or CARD domain (CARD-only) posses an obvious potential ability to act as competitive inhibitors of NLR complexes. Indeed, both Pyrin-only proteins (POPs) and CARD-only proteins (COPs) have been described as regulators of caspase-1 and/or NLR-inflammasome activation and not surprisingly as factors mediating pathogenesis. Although clear examples of pathogen encoded POPs are currently limited to members of the poxviridae, the human genome likely encodes three POPs (POP1, POP2, and a potential POP3), of which only POP2 is known to prevent NLR:ASC interaction, and three COPs (COP/Pseudo-ICE, INCA, and ICEBERG), initially described for their ability to inhibit caspase-1 activity. Surprisingly, among eukaryotic species POPs and COPs appear to be evolutionarily recent and restricted to higher primates, suggesting strong selective pressures driving their emergence. Despite the importance of understanding the regulation of NLR functions, relatively little attention has been devoted to revealing the biological impact of these intriguing proteins. This review highlights the current state of our understanding of POPs and COPs with attention to protein interaction, functions, evolution, implications for health and disease, and outstanding questions.
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