Our innate immune system distinguishes microbes from self by detecting conserved pathogen-associated molecular patterns1. However, these are produced by all microbes, regardless of their pathogenic potential. To distinguish virulent microbes from those with lower disease-causing potential the innate immune system detects conserved pathogen-induced processes2, such as the presence of microbial products in the host cytosol, by mechanisms that are not fully resolved. Here we show that NOD1 senses cytosolic microbial products by monitoring the activation state of small Rho GTPases. Activation of RAC1 and CDC42 by bacterial delivery or ectopic expression of SopE, a virulence factor of the enteric pathogen Salmonella, triggered the NOD1 signalling pathway, with consequent RIP2 (also known as RIPK2)-mediated induction of NF-κB-dependent inflammatory responses. Similarly, activation of the NOD1 signalling pathway by peptidoglycan required RAC1 activity. Furthermore, constitutively active forms of RAC1, CDC42 and RHOA activated the NOD1 signalling pathway. Our data identify the activation of small Rho GTPases as a pathogen-induced process sensed through the NOD1 signalling pathway.
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We would like to thank S.-P. Nuccio for providing PCR primers for the construction of the bacterial strains. This work was supported by Public Health Service Grants AI044170 and AI076246. A.M.K. is supported by the American Heart Association Grant 12SDG12220022.
The authors declare no competing financial interests.
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Keestra, A., Winter, M., Auburger, J. et al. Manipulation of small Rho GTPases is a pathogen-induced process detected by NOD1. Nature 496, 233–237 (2013). https://doi.org/10.1038/nature12025
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