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Infection and Immunity, June 2006, p. 3115-3124, Vol. 74, No. 6
0019-9567/06/$08.00+0     doi:10.1128/IAI.00035-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role for Erbin in Bacterial Activation of Nod2

T. A. Kufer,1 E. Kremmer,2 D. J. Banks,1 and D. J. Philpott1*

Immunité Innée et Signalisation, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris, France,1 GSF—Institut für Molekulare Immunologie, Marchioninistrasse 25, 81377 München, Germany2

Received 7 January 2006/ Returned for modification 24 February 2006/ Accepted 2 March 2006

Intracellular peptidoglycan (PG) recognition in human cells is mediated by the NACHT-LRR proteins Nod1 and Nod2. Elicitation of these proteins by PG motifs released from invasive bacteria triggers signaling events, resulting in the activation of the NF-{kappa}B pathway. In order to decipher the molecular components involved in Nod2 signal transduction, we set out to identify new interaction partners of Nod2 by using a yeast two-hybrid screen. Besides the known interaction partner RIP2, the screen identified the leucine-rich repeat (LRR)- and PDZ domain-containing family member Erbin as a binding partner of Nod2. Erbin showed a specific interaction with Nod2 in coimmunoprecipitation experiments with human HEK 293T cells. Immunofluorescence microscopy with a newly generated anti-Nod2 monoclonal antibody showed that Erbin and Nod2 partially colocalize in human cells. Subsequent analysis of the Erbin/Nod2 interaction revealed that the LRR of Erbin and the caspase activating and recruiting domains of Nod2 were necessary for this interaction. No significant interaction was observed with a Walker B box mutant of Nod2 or a Crohn's disease-associated frameshift mutant of Nod2, indicating that complex formation is dependent on the activity of the molecule. In addition, a change in the dynamics of the Erbin/Nod2 complex was observed during Shigella flexneri infection. Furthermore, ectopic expression of increasing amounts of Erbin or short hairpin RNA-mediated knockdown of Erbin showed a negative influence of Erbin on Nod2/muramyl-dipeptide-mediated NF-{kappa}B activation. These results implicate Erbin as a potential negative regulator of Nod2 and show that bacterial infection has an impact on Nod2/Erbin complex formation within cells.

* Corresponding author. Present address: Department of Immunology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Phone: (416) 978-7527. Fax: (416) 978-1938. E-mail: dana.philpott{at}utoronto.ca.

Editor: J. N. Weiser

Infection and Immunity, June 2006, p. 3115-3124, Vol. 74, No. 6
0019-9567/06/$08.00+0     doi:10.1128/IAI.00035-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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