Inflammatory caspases are innate immune receptors for intracellular LPS

Jianjin Shi, Yue Zhao, Yupeng Wang, Wenqing Gao, Jingjin Ding, Peng Li, Liyan Hu and Feng Shao ()
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Jianjin Shi: Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, National Institute of Biological Sciences
Yue Zhao: National Institute of Biological Sciences
Yupeng Wang: National Institute of Biological Sciences
Wenqing Gao: National Institute of Biological Sciences
Jingjin Ding: National Institute of Biological Sciences
Peng Li: National Institute of Biological Sciences
Liyan Hu: National Institute of Biological Sciences
Feng Shao: Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, National Institute of Biological Sciences

Nature, 2014, vol. 514, issue 7521, 187-192

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/nature13683

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