Inflammatory caspases are innate immune receptors for intracellular LPS - PubMed

Affiliations

• PMID: 25119034
• DOI: 10.1038/nature13683

Inflammatory caspases are innate immune receptors for intracellular LPS

Jianjin Shi et al. Nature. 2014.

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.

Comment in

• Host response: new LPS receptors discovered.

  Nunes-Alves C. Nunes-Alves C. Nat Rev Microbiol. 2014 Oct;12(10):658. doi: 10.1038/nrmicro3345. Epub 2014 Aug 19. Nat Rev Microbiol. 2014. PMID: 25134619 No abstract available.

• Inflammasomes: new LPS receptors discovered.

  Nunes-Alves C. Nunes-Alves C. Nat Rev Immunol. 2014 Sep;14(9):582. doi: 10.1038/nri3736. Nat Rev Immunol. 2014. PMID: 25145754 No abstract available.

• WildCARDs: inflammatory caspases directly detect LPS.

  Hagar JA, Aachoui Y, Miao EA. Hagar JA, et al. Cell Res. 2015 Feb;25(2):149-50. doi: 10.1038/cr.2014.128. Epub 2014 Sep 30. Cell Res. 2015. PMID: 25267404 Free PMC article.

• Caspases come together over LPS.

  Smith C, Wang X, Yin H. Smith C, et al. Trends Immunol. 2015 Feb;36(2):59-61. doi: 10.1016/j.it.2014.12.007. Epub 2015 Jan 5. Trends Immunol. 2015. PMID: 25573609 Free PMC article.

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