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Inflammatory caspases are innate immune receptors for intracellular LPS

机译：炎性胱天蛋白酶是细胞内LPS的先天免疫受体

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摘要

The murine caspase-11 non-canonical inflammasome responds to various bacterial infections. Caspase-11 activation-induced pyroptosis, in response to cytoplasmic lipopolysaccharide (LPS), is critical for endotoxic shock in mice. The mechanism underlying cytosolic LPS sensing and the responsible pattern recognition receptor are unknown. Here we show that human monocytes, epithelial cells and keratinocytes undergo necrosis upon cytoplasmic delivery of LPS. LPS-induced cytotoxicity was mediated by human caspase-4 that could functionally complement murine caspase-11. Human caspase-4 and the mouse homologue caspase-11 (hereafter referred to as caspase-4/11) and also human caspase-5, directly bound to LPS and lipid A with high specificity and affinity. LPS associated with endogenous caspase-11 in pyroptotic cells. Insect-cell purified caspase-4/11 underwent oligomerization upon LPS binding, resulting in activation of the caspases. Underacylated lipid Iva and lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) could bind to caspase-4/11 but failed to induce their oligomerization and activation. LPS binding was mediated by the CARD domain of the caspase. Binding-deficient CARD-domain point mutants did not respond to LPS with oligomerization or activation and failed to induce pyroptosis upon LPS electroporation or bacterial infections. The function of caspase-4/5/11 represents a new mode of pattern recognition in immunity and also an unprecedented means of caspase activation.%一个"非经典"先天免疫通道(独立于"Toll-样受体-4"、但涉及半胱天冬酶-11)最近在小鼠身上被发现，在那里其作用是识别来自致病细菌的脂多糖(LPS)。在这篇论文中，Feng Shao及同事对这一通道和人类身上一个类似的通道进行了研究。他们发现，半胱天冬酶-11和半胱天冬酶-4分别是小鼠和人类的胞质LPS的直接传感器，在细胞内细菌感染中介导炎性细胞死亡。
机译：鼠caspase-11非典型炎症小体对各种细菌感染有反应。 Caspase-11激活诱导的细胞凋亡，对细胞质脂多糖（LPS）的响应，对于小鼠内毒素休克至关重要。尚不清楚胞质LPS感知和负责的模式识别受体的潜在机制。在这里，我们显示人单核细胞，上皮细胞和角质形成细胞在LPS的细胞质传递后发生坏死。 LPS诱导的细胞毒性是由人caspase-4介导的，它可以在功能上与鼠caspase-11互补。人caspase-4和小鼠同源物caspase-11（以下称为caspase-4 / 11）以及人caspase-5以高特异性和亲和性直接结合于LPS和脂质A。 LPS与焦磷酸细胞中的内源性caspase-11相关。昆虫细胞纯化的caspase-4 / 11在LPS结合后发生寡聚，导致胱天蛋白酶激活。球形红球菌（LPS-RS）的酰化不足的脂质Iva和脂多糖可以与caspase-4 / 11结合，但不能诱导它们的寡聚和活化。 LPS结合是由caspase的CARD结构域介导的。结合缺陷的CARD域点突变体不响应LPS的低聚或激活，并且在LPS电穿孔或细菌感染后无法诱导焦磷酸化。 caspase-4 / 5/11的功能代表了免疫模式识别的新模式，也是caspase激活的空前手段。％一个“非经典”先天免疫通道（独立于“ Toll-样受体-4”，但涉及半胱氨酸天冬酶-11）最近在小鼠身上被发现，而其作用是识别来自致病细菌的脂质葡萄糖（LPS）。在本文中，Feng Shao及同事对这一通道和他们发现，半胱氨酸天冬酶-11和半胱氨酸天冬酶-4分别是小鼠和人类的胞质LPS的直接传感器，在细胞内细菌感染中介导炎性细胞死亡。

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  • 来源
    《Nature》 |2014年第7521期|187-192a1|共7页
  • 作者

    Jianjin Shi; Yue Zhao; Yupeng Wang; Wenqing Gao; Jingjin Ding; Peng Li; Liyan Hu; Feng Shao;

  • 作者单位

    Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, National Institute of Biological Sciences, Beijing 102206, China,National Institute of Biological Sciences, Beijing 102206, China;

    National Institute of Biological Sciences, Beijing 102206, China;

    National Institute of Biological Sciences, Beijing 102206, China;

    National Institute of Biological Sciences, Beijing 102206, China;

    National Institute of Biological Sciences, Beijing 102206, China,National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;

    National Institute of Biological Sciences, Beijing 102206, China;

    National Institute of Biological Sciences, Beijing 102206, China;

    Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, National Institute of Biological Sciences, Beijing 102206, China,National Institute of Biological Sciences, Beijing 102206, China,National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China,National Institute of Biological Sciences, Beijing, Collaborative Innovation Center for Cancer Medicine, Beijing 102206, China;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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