Hypoxia and the hypoxic response pathway protect against pore-forming toxins in C. elegans.
Hypoxia and the hypoxic response pathway protect against pore-forming toxins in C. elegans.
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DOI：
10.1371/journal.ppat.1000689
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发表时间：
2009-12
期刊：
影响因子：
6.7
通讯作者：
Aroian RV
中科院分区：
文献类型：
--
作者：
Bellier A;Chen CS;Kao CY;Cinar HN;Aroian RV
孔形成毒素（PFT）是迄今为止最丰富的细菌蛋白毒素，并且对于许多重要病原体的毒力是重要的。因此，细胞对PFT的反应严重调节宿主-病原体相互作用。虽然许多细胞反应PFT已被记录，很少有人了解他们的病理或防御结果的相关性。为了阐明这一重要问题，我们转向了研究PFT-宿主相互作用的唯一遗传系统-秀丽隐杆线虫被晶体（Cry）蛋白PFT中毒。我们诱变并筛选了C。elegans突变体对Cry PFT具有抗性，并回收了一个突变体。互补、测序、转基因拯救和RNA干扰数据表明，该突变体消除了通常参与低氧（低氧反应）途径抑制的基因。我们发现C.通过失活通常抑制该途径的三种不同基因，通过线虫缺氧途径导致动物对Cry PFT具有抗性。相反，缺氧反应的中枢激活因子HIF-1的突变抑制了这种抵抗力，并可能导致动物在PFT防御方面有缺陷。这些结果扩展到PFT攻击哺乳动物，因为缺氧途径的上调赋予对霍乱弧菌溶细胞素（VCC）的抗性，而下调赋予过敏性。低氧PFT防御途径是细胞自主的保护细胞免受攻击的直接途径，与其他低氧应激反应途径不同。该通路的两个下游效应物包括核受体nhr-57和未折叠蛋白反应。此外，缺氧途径本身是由PFT诱导的，低氧对PFT中毒具有保护作用。这些结果表明，缺氧和缺氧反应的诱导保护细胞免受PFT，并且细胞环境可以通过缺氧途径调节以保护免受病原菌使用的最普遍的武器类别。细菌制造许多不同的蛋白质毒素来攻击我们的细胞和免疫系统，以感染。其中，孔形成毒素（PFT）在细胞周围的保护性质膜上穿孔，是迄今为止最丰富的，并构成重要的毒力因子。由于质膜的完整性是维持正常细胞内环境的基础，PFT对质膜的破坏导致许多显著的细胞内反应。然而，我们对这些反应与细胞存活或细胞中毒的相关性知之甚少。在这里，我们使用唯一的遗传系统来研究整个动物中的成孔毒素效应，我们表明，保护细胞免受低氧应激的相同反应也意外地保护细胞免受成孔毒素的影响。在动物中，超激活低氧反应的突变实际上使动物抵抗成孔毒素的攻击，而抑制低氧反应的突变使动物更容易受到影响。此外，低氧环境本身可以防止毛孔形成毒素。这些数据显示了低氧反应和防御细菌攻击的单一最常见模式之间的新的和强大的联系。
Pore-forming toxins (PFTs) are by far the most abundant bacterial protein toxins and are important for the virulence of many important pathogens. As such, cellular responses to PFTs critically modulate host-pathogen interactions. Although many cellular responses to PFTs have been recorded, little is understood about their relevance to pathological or defensive outcomes. To shed light on this important question, we have turned to the only genetic system for studying PFT-host interactions—Caenorhabditis elegans intoxication by Crystal (Cry) protein PFTs. We mutagenized and screened for C. elegans mutants resistant to a Cry PFT and recovered one mutant. Complementation, sequencing, transgenic rescue, and RNA interference data demonstrate that this mutant eliminates a gene normally involved in repression of the hypoxia (low oxygen response) pathway. We find that up-regulation of the C. elegans hypoxia pathway via the inactivation of three different genes that normally repress the pathway results in animals resistant to Cry PFTs. Conversely, mutation in the central activator of the hypoxia response, HIF-1, suppresses this resistance and can result in animals defective in PFT defenses. These results extend to a PFT that attacks mammals since up-regulation of the hypoxia pathway confers resistance to Vibrio cholerae cytolysin (VCC), whereas down-regulation confers hypersusceptibility. The hypoxia PFT defense pathway acts cell autonomously to protect the cells directly under attack and is different from other hypoxia pathway stress responses. Two of the downstream effectors of this pathway include the nuclear receptor nhr-57 and the unfolded protein response. In addition, the hypoxia pathway itself is induced by PFT, and low oxygen is protective against PFT intoxication. These results demonstrate that hypoxia and induction of the hypoxia response protect cells against PFTs, and that the cellular environment can be modulated via the hypoxia pathway to protect against the most prevalent class of weapons used by pathogenic bacteria. Bacteria make many different protein toxins to attack our cells and immune system in order to infect. Amongst them, pore-forming toxins (PFTs), which punch holes in the protective plasma membrane that surrounds cells, are by far the most abundant and constitute important virulence factors. Since the integrity of the plasma membrane is fundamental to maintaining the normal intracellular environment, the breaching of the plasma membrane by PFTs results in many and dramatic intracellular responses. However, we know little about the relevance of these responses to cell survival or cell intoxication. Here, using the only genetic system for studying pore-forming toxin effects in a whole animal, we show that the same response that protects cells against low oxygen stress unexpectedly also protects cells against pore-forming toxins. Mutations in the animal that hyper-activate the low oxygen response actually make animals resistant to pore-forming toxin attack, whereas mutations that inactivate the low oxygen response make animals more susceptible. Furthermore, a low oxygen environment itself is protective against pore-forming toxins. These data show a new and powerful connection between low oxygen responses and defense against the single most common mode of bacterial attack.
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影响因子：
64.5
作者：
Gurcel, Laure;Abrami, Laurence;van der Goot, F. Gisou
通讯作者：
van der Goot, F. Gisou
影响因子：
4.8
作者：
Griffitts, JS;Huffman, DL;Aroian, RV
通讯作者：
Aroian, RV
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
DOI：
10.1073/pnas.96.26.15202
发表时间：
1999-12-21
影响因子：
11.1
作者：
Darby, C;Cosma, CL;Manoil, C
通讯作者：
Manoil, C
影响因子：
5.6
作者：
Britton, C;McKerrow, JH;Johnstone, LL
通讯作者：
Johnstone, LL