Dissecting the role of the Tir:Nck and Tir:IRTKS/IRSp53 signalling pathways in vivo

Crepin, Valérie F., Girard, Francis, Schuller, Stephanie ORCID: https://orcid.org/0000-0003-3260-9112, Phillips, Alan D., Mousnier, Aurelie and Frankel, Gad (2010) Dissecting the role of the Tir:Nck and Tir:IRTKS/IRSp53 signalling pathways in vivo. Molecular Microbiology, 75 (2). pp. 308-323. ISSN 1365-2958

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Abstract

Attaching and effacing (A/E) lesions and actin polymerization, the hallmark of enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC) and Citrobacter rodentium (CR) infections, are dependent on the effector Tir. Phosphorylation of TirEPEC/CR Y474/1 leads to recruitment of Nck and neural Wiskott–Aldrich syndrome protein (N-WASP) and strong actin polymerization in cultured cells. TirEPEC/CR also contains an Asn-Pro-Tyr (NPY454/1) motif, which triggers weak actin polymerization. In EHEC the NPY458 actin polymerization pathway is amplified by TccP/EspFU, which is recruited to Tir via IRSp53 and/or insulin receptor tyrosine kinase substrate (IRTKS). Here we used C. rodentium to investigate the different Tir signalling pathways in vivo. Following infection with wild-type C. rodentium IRTKS, but not IRSp53, was recruited to the bacterial attachment sites. Similar results were seen after infection of human ileal explants with EHEC. Mutating Y471 or Y451 in TirCR abolished recruitment of Nck and IRTKS respectively, but did not affect recruitment of N-WASP or A/E lesion formation. This suggests that despite their crucial role in actin polymerization in cultured cells the Tir:Nck and Tir:IRTKS pathways are not essential for N-WASP recruitment or A/E lesion formation in vivo. Importantly, wild-type C. rodentium out-competed the tir tyrosine mutants during mixed infections. These results uncouple the Tir:Nck and Tir:IRTKS pathways from A/E lesion formation in vivo but assign them an important in vivo role.

Item Type:	Article
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Pathogen Biology Group
Depositing User:	Rhiannon Harvey
Date Deposited:	22 Mar 2011 16:44
Last Modified:	24 Sep 2024 09:11
URI:	https://ueaeprints.uea.ac.uk/id/eprint/26927
DOI:	10.1111/j.1365-2958.2009.06938.x

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