EMBO Rep. 2001 Aug;2(8):736-42. Epub 2001 Jul 19.

CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri.External

Girardin, S. E., Tournebize, R., Mavris, M., Page, A. L., Li, X., Stark, G. R., Bertin, J., DiStefano, P. S., Yaniv, M., Sansonetti, P. J., Philpott, D. J.,
--- - Unite des Virus Oncogenes, and Unite INSERM 389, Institut Pasteur, 28 rue du Dr Roux, Paris, Cedex 15, 75724 France.
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.
PMID: 11463746External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
CARD NOD1 Link RIPK2 Co-immunoprecipitation HEK293 Human Full length Not specified Not specified 11463746
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
Functional Role
Family DD1 DD2 Method Death-related Death-unrelated Reference
CARD NOD1 Link RIPK2 Reporter gene assay NF-kB activation (Nodosome) 11463746
(Link: click this icon to show interactions only between the two corresponding DDs)