title: Manipulation of small Rho GTPases is a pathogen-induced process detected by NOD1.
abstract: Our innate immune system distinguishes microbes from self by detecting conserved pathogen-associated molecular patterns. 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 processes, 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.
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, California 95616, USA.
authors.forename: A Marijke
authors.initials: AM
authors.lastname: Keestra
authors.forename: Maria G
authors.initials: MG
authors.lastname: Winter
authors.forename: Josef J
authors.initials: JJ
authors.lastname: Auburger
authors.forename: Simon P
authors.initials: SP
authors.lastname: Frässle
authors.forename: Mariana N
authors.initials: MN
authors.lastname: Xavier
authors.forename: Sebastian E
authors.initials: SE
authors.lastname: Winter
authors.forename: Anita
authors.initials: A
authors.lastname: Kim
authors.forename: Victor
authors.initials: V
authors.lastname: Poon
authors.forename: Mariëtta M
authors.initials: MM
authors.lastname: Ravesloot
authors.forename: Julian F T
authors.initials: JF
authors.lastname: Waldenmaier
authors.forename: Renée M
authors.initials: RM
authors.lastname: Tsolis
authors.forename: Richard A
authors.initials: RA
authors.lastname: Eigenheer
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Bäumler
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D010457:Peptidoglycan / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism; D012486:Salmonella typhimurium / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D015398:Signal Transduction; D037521:Virulence Factors / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D018841:HSP90 Heat-Shock Proteins; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan; C103987:SopE protein, Salmonella; D037521:Virulence Factors; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
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