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PLoS Pathog DOI:10.1371/journal.ppat.1001332

Bacterial and host determinants of MAL activation upon EPEC infection: the roles of Tir, ABRA, and FLRT3.

Publication TypeJournal Article
Year of Publication2011
AuthorsHeath, RJW, Leong, JM, Visegrády, B, Machesky, LM, Xavier, RJ
JournalPLoS Pathog
Date Published2011 Apr
KeywordsActins, Animals, Bacterial Adhesion, Cercopithecus aethiops, COS Cells, Cytoskeleton, Enteropathogenic Escherichia coli, Epithelial Cells, Escherichia coli Infections, Escherichia coli Proteins, Intestines, Membrane Proteins, Membrane Transport Proteins, Microfilament Proteins, Myelin and Lymphocyte-Associated Proteolipid Proteins, Myelin Proteins, Phosphorylation, Protein Binding, Protein Transport, Proteolipids, Receptors, Cell Surface, Signal Transduction, Transcription Factors, Tyrosine

Infection of host cells by pathogenic microbes triggers signal transduction pathways leading to a multitude of host cell responses including actin cytoskeletal re-arrangements and transcriptional programs. The diarrheagenic pathogens Enteropathogenic E. coli (EPEC) and the related Enterohemorrhagic E. coli (EHEC) subvert the host-cell actin cytoskeleton to form attaching and effacing lesions on the surface of intestinal epithelial cells by injecting effector proteins via a type III secretion system. Here we use a MAL translocation assay to establish the effect of bacterial pathogens on host cell signaling to transcription factor activation. MAL is a cofactor of Serum response factor (SRF), a transcription factor with important roles in the regulation of the actin cytoskeleton. We show that EPEC induces nuclear accumulation of MAL-GFP. The translocated intimin receptor is essential for this process and phosphorylation of Tyrosine residues 454 and 474 is important. Using an expression screen we identify FLRT3, C22orf28 and TESK1 as novel activators of SRF. Importantly we demonstrate that ABRA (actin-binding Rho-activating protein, also known as STARS) is necessary for EPEC-induced nuclear accumulation of MAL and the novel SRF activator FLRT3, is a component of this pathway. We further demonstrate that ABRA is important for structural maintenance of EPEC pedestals. Our results uncover novel components in pathogen-activated cytoskeleton signalling to MAL activation.


Alternate JournalPLoS Pathog.
PubMed ID21490959
PubMed Central IDPMC3072376
Grant ListAI062773 / AI / NIAID NIH HHS / United States
P30 DK040561 / DK / NIDDK NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
R01 AI046454 / AI / NIAID NIH HHS / United States
P30 DK040561-15 / DK / NIDDK NIH HHS / United States
DK83756 / DK / NIDDK NIH HHS / United States
R01-AI46454 / AI / NIAID NIH HHS / United States
R01 AI062773 / AI / NIAID NIH HHS / United States
G117/569 / / Medical Research Council / United Kingdom
DK 043351 / DK / NIDDK NIH HHS / United States
R01 DK083756 / DK / NIDDK NIH HHS / United States