CARD4/Nod1 mediates NF-|[kappa]|B and JNK activation by invasive Shigella flexneri

Unité des Virus Oncogènes, and Unité INSERM 389, Institut Pasteur, 28 rue du Dr Roux, Paris, Cédex 15, 75724 France.
EMBO Reports (Impact Factor: 9.06). 07/2001; 2(8):736-742. DOI: 10.1093/embo-reports/kve155
Source: PubMed


Epithelial cells are refractory to extracellular lipopolysaccharide (LPS), yet when presented inside the cell, it is capable of initiating an inflammatory response. Using invasive Shigella flexneri to deliver LPS into the cytosol, we examined how this factor, once intracellular, activates both NF-kappaB and c-Jun N-terminal kinase (JNK). Surprisingly, the mode of activation is distinct from that induced by toll-like receptors (TLRs), which mediate LPS responsiveness from the outside-in. Instead, our findings demonstrate that this response is mediated by a cytosolic, plant disease resistance-like protein called CARD4/Nod1. Biochemical studies reveal enhanced oligomerization of CARD4 upon S. flexneri infection, an event necessary for NF-kappaB induction. Dominant-negative versions of CARD4 block activation of NF-kappaB and JNK by S. flexneri as well as microinjected LPS. Finally, we showed that invasive S. flexneri triggers the formation of a transient complex involving CARD4, RICK and the IKK complex. This study demonstrates that in addition to the extracellular LPS sensing system mediated by TLRs, mammalian cells also possess a cytoplasmic means of LPS detection via a molecule that is related to plant disease-resistance proteins.

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Available from: Moshe Yaniv
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    • "We employed Shigella flexneri, an invasive Gram-negative enteropathogenic bacterium, as an infection model to study the complex host–pathogen interactions that shape the immune response of intestinal epithelial cells in response to bacterial infection . The host response to intracellular Shigella involves NOD1 signaling followed by activation of RIPK2, leading to the activation of NF-jB and the production and secretion of pro-inflammatory cytokines such as IL-8 (Girardin et al, 2001). However, Shigella has evolved a number of strategies to actively down-regulate the host cell immune response to ensure bacterial survival and propagation within the human intestinal epithelium. "
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    • "Intestinal pathogens such as Salmonella and Shigella have been shown to activate NFκB in intestinal epithelial cells in a TLR independent manner. For example, Shigella flexneri invades and activates NOD1, which senses bacterial peptidoglycan, leading to IL-8 production [35]. In Salmonella, the T3SS effector SopE activates NFκB [36] by engaging small Rho GTPases CDC42 and Rac1, which in turn trigger NOD1 and RIP2 activation of NFκB [25]. "
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    • "Upon ligand recognition, the NBD domain of NOD1 or NOD2 oligomerizes and initiates the interaction of the CARD domain with RIPK2 (also called RIP2/RICK), which is a member of the CARD protein family [49,55]. RIPK2 is activated subsequently by proximity and promotes the formation of a signaling complex that contains the regulatory subunit of the IKK complex, NEMO [64], leading to NF-κB activation (see Figure  2, left panel). "
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