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Nature:半胱天冬酶在先天免疫中的传感作用

摘要 : 北大-清华-国家生物科学联合研究生课程研究所的研究人员在新研究中发现,半胱天冬酶-11和半胱天冬酶-4分别是小鼠和人类的胞质脂多糖的直接传感器,在细胞内细菌感染中介导炎性细胞死亡。相关文章发表于2014年8月6日的《Nature》杂志上。

LPS结合诱导低聚合反应是激活半胱天冬酶-4/11所需的。

LPS结合诱导低聚合反应是激活半胱天冬酶-4/11所需的。

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。

原文摘要:

Inflammatory caspases are innate immune receptors for intracellular LPS

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

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.

对应Nature杂志: 2014年10月9日Nature杂志精选

来源: Nature中文 浏览次数:239

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