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CARD4/Nod1 mediates NF‐κB and JNK activation by invasive Shigella flexneri
Author(s) -
Girardin Stephen E,
Tournebize Régis,
Mavris Maria,
Page AnneLaure,
Li Xiaoxia,
Stark George R,
Bertin John,
DiStefano Peter S,
Yaniv Moshe,
Sansonetti Philippe J,
Philpott Dana J
Publication year - 2001
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1093/embo-reports/kve155
Subject(s) - shigella flexneri , nod1 , nf κb , microbiology and biotechnology , shigella , biology , signal transduction , immunology , bacteria , escherichia coli , nod2 , salmonella , innate immune system , immune system , biochemistry , genetics , gene
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‐κB 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‐κB induction. Dominant‐negative versions of CARD4 block activation of NF‐κB 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.