NLR家族凋亡抑制蛋白的特异性作用
炎性体（即inflammasomes，它们是先天免疫中所涉及的多蛋白复合物）通过激发caspase-1蛋白酶诱导针对致病微生物的免疫反应。现在，两个小组报告，被称为NAIPs（NLR家族的凋亡抑制蛋白）的细胞内受体（以前被认为在识别微生物蛋白中有辅助作用）事实上在该过程中起中心作用。Eric Kofoed 和 Russell Vance以及Feng Shao和同事发现，NLR家族的不同成员与不同的细菌配体相结合，包括细菌鞭毛蛋白和一个保守的细菌性Type III分泌系统杆蛋白。
Inflammasomes are a family of cytosolic multiprotein complexes that initiate innate immune responses to pathogenic microbes by activating the caspase 1 protease. Although genetic data support a critical role for inflammasomes in immune defence and inflammatory diseases, the molecular basis by which individual inflammasomes respond to specific stimuli remains poorly understood. The inflammasome that contains the NLRC4 (NLR family, CARD domain containing 4) protein was previously shown to be activated in response to two distinct bacterial proteins, flagellin and PrgJ, a conserved component of pathogen-associated type III secretion systems. However, direct binding between NLRC4 and flagellin or PrgJ has never been demonstrated. A homologue of NLRC4, NAIP5 (NLR family, apoptosis inhibitory protein 5), has been implicated in activation of NLRC4 (refs 7–11), but is widely assumed to have only an auxiliary role, as NAIP5 is often dispensable for NLRC4 activation. However, Naip5 is a member of a small multigene family, raising the possibility of redundancy and functional specialization among Naip genes. Here we show in mice that different NAIP paralogues determine the specificity of the NLRC4 inflammasome for distinct bacterial ligands. In particular, we found that activation of endogenous NLRC4 by bacterial PrgJ requires NAIP2, a previously uncharacterized member of the NAIP gene family, whereas NAIP5 and NAIP6 activate NLRC4 specifically in response to bacterial flagellin. We dissected the biochemical mechanism underlying the requirement for NAIP proteins by use of a reconstituted NLRC4 inflammasome system. We found that NAIP proteins control ligand-dependent oligomerization of NLRC4 and that the NAIP2–NLRC4 complex physically associates with PrgJ but not flagellin, whereas NAIP5–NLRC4 associates with flagellin but not PrgJ. Our results identify NAIPs as immune sensor proteins and provide biochemical evidence for a simple receptor–ligand model for activation of the NAIP–NLRC4 inflammasomes.
第一个爬行动物基因组公布
第一个非禽类爬行动物的基因组已被测序，它就是北美绿色安乐蜥（Anolis carolinensis）的基因组。安乐蜥是研究适应性辐射和趋同进化的一个新兴模型生物。它的基因组包括一个以前不知道的与已知脊椎动物性染色体都不同源的X-染色体，同时还包括一些微染色体，它们与鸟类的微染色体有共同祖先、但却没有其不寻常特点。
he evolution of the amniotic egg was one of the great evolutionary innovations in the history of life, freeing vertebrates from an obligatory connection to water and thus permitting the conquest of terrestrial environments. Among amniotes, genome sequences are available for mammals and birds, but not for non-avian reptiles. Here we report the genome sequence of the North American green anole lizard, Anolis carolinensis. We find that A. carolinensis microchromosomes are highly syntenic with chicken microchromosomes, yet do not exhibit the high GC and low repeat content that are characteristic of avian microchromosomes. Also, A. carolinensis mobile elements are very young and diverse—more so than in any other sequenced amniote genome. The GC content of this lizard genome is also unusual in its homogeneity, unlike the regionally variable GC content found in mammals and birds. We describe and assign sequence to the previously unknown A. carolinensis X chromosome. Comparative gene analysis shows that amniote egg proteins have evolved significantly more rapidly than other proteins. An anole phylogeny resolves basal branches to illuminate the history of their repeated adaptive radiations.
Tet3对受精卵的重新编程
一个合子（受精卵）中的父方基因组，在雄性和雌性原核融合之前经历活跃的DNA去甲基化，这一过程与5-甲基胞嘧啶(5mC)被氧化成5-羟甲基胞嘧啶(5hmC)的过程同时发生。在这项研究中，Gu等人培育出了缺少双加氧酶Tet3的催化活性的基因剔除小鼠。在缺失Tet3的合子中，父方基因组中5mC向5hmC的转化未能出现，而且5mC的水平保持不变。另外，父方Oct4和Nanog基因的去甲基化也受阻。因此，Tet3-调控的5mC氧化有助于合子父方基因组中的去甲基化和基因激发。
Sperm and eggs carry distinctive epigenetic modifications that are adjusted by reprogramming after fertilization. The paternal genome in a zygote undergoes active DNA demethylation before the first mitosis. The biological significance and mechanisms of this paternal epigenome remodelling have remained unclear4. Here we report that, within mouse zygotes, oxidation of 5-methylcytosine (5mC) occurs on the paternal genome, changing 5mC into 5-hydroxymethylcytosine (5hmC). Furthermore, we demonstrate that the dioxygenase Tet3 (ref. 5) is enriched specifically in the male pronucleus. In Tet3-deficient zygotes from conditional knockout mice, paternal-genome conversion of 5mC into 5hmC fails to occur and the level of 5mC remains constant. Deficiency of Tet3 also impedes the demethylation process of the paternal Oct4 and Nanog genes and delays the subsequent activation of a paternally derived Oct4 transgene in early embryos. Female mice depleted of Tet3 in the germ line show severely reduced fecundity and their heterozygous mutant offspring lacking maternal Tet3 suffer an increased incidence of developmental failure. Oocytes lacking Tet3 also seem to have a reduced ability to reprogram the injected nuclei from somatic cells. Therefore, Tet3-mediated DNA hydroxylation is involved in epigenetic reprogramming of the zygotic paternal DNA following natural fertilization and may also contribute to somatic cell nuclear reprogramming during animal cloning.
