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      Bacterial and Host Determinants of MAL Activation upon EPEC Infection: The Roles of Tir, ABRA, and FLRT3

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          Abstract

          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.

          Author Summary

          Many significant immune diseases are caused by bacterial pathogens that deliver effector proteins into their host. The pathogen uses these proteins to subvert the hosts' normal cytosolic defense in a way that services the pathogen. It is therefore important to understand the normal processes of a cell and how they are affected by bacterial infection. We have established the effect of bacteria on host cell signalling to the transcription factor serum response factor. Serum response factor is a widely expressed transcription factor that controls the expression of many important genes. We show that Enteropathogenic E. coli infection can activate serum response factor and that the effector protein Tir is essential for this activation. Furthermore, we identify new genes that are important in this infection-induced activation and show that they are important in maintaining structures necessary for Enteropathogenic E. coli infection.

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          Most cited references 41

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          Enteropathogenic E. coli (EPEC) transfers its receptor for intimate adherence into mammalian cells.

          Enteropathogenic E. coli (EPEC) belongs to a group of bacterial pathogens that induce epithelial cell actin rearrangements resulting in pedestal formation beneath adherent bacteria. This requires the secretion of specific virulence proteins needed for signal transduction and intimate adherence. EPEC interaction induces tyrosine phosphorylation of a protein in the host membrane, Hp90, which is the receptor for the EPEC outer membrane protein, intimin. Hp90-intimin interaction is essential for intimate attachment and pedestal formation. Here, we demonstrate that Hp90 is actually a bacterial protein (Tir). Thus, this bacterial pathogen inserts its own receptor into mammalian cell surfaces, to which it then adheres to trigger additional host signaling events and actin nucleation. It is also tyrosine-phosphorylated upon transfer into the host cell.
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            Actin' together: serum response factor, its cofactors and the link to signal transduction.

            The vast diversity of cellular types and behaviours is mainly the result of combinatorial interactions between a limited number of transcription factors and cellular signalling pathways whose activity is stringently controlled by developmental, cellular and extracellular cues. Studies of serum response factor (SRF) have provided a paradigm for such interactions for some years. Recent advances have shown that two families of SRF cofactors, the ternary complex factors (TCFs) and the myocardin-related transcription factors (MTRFs), are regulated by separate signalling pathways and thereby control SRF target genes differentially. The actin cytoskeleton is both an upstream regulator of MRTF activity, with monomeric actin directly acting as a signal transducer, and a downstream effector, because of the many cytoskeletal target genes. Here we discuss how the competition among cofactors might integrate these distinct signalling pathways into a specific transcriptional response and biological function.
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              The Rho family GTPases RhoA, Racl , and CDC42Hsregulate transcriptional activation by SRF

              Cell, 81(7), 1159-1170
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                April 2011
                April 2011
                7 April 2011
                : 7
                : 4
                Affiliations
                [1 ]Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
                [2 ]Gastrointestinal Unit, Center for Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
                [3 ]Department of Molecular Genetics and Microbiology, UMass Medical School, Worcester, Massachusetts, United States of America
                [4 ]Beatson Institute for Cancer Research, Garscube Estate, Bearsden, Glasgow, United Kingdom
                [5 ]The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
                University of Helsinki, Finland
                Author notes

                Conceived and designed the experiments: RJWH JML RJX. Performed the experiments: RJWH. Analyzed the data: RJWH. Contributed reagents/materials/analysis tools: JML BV LMM. Wrote the paper: RJWH.

                Article
                10-PLPA-RA-3800R3
                10.1371/journal.ppat.1001332
                3072376
                21490959
                Heath et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 15
                Categories
                Research Article
                Cell Biology
                Cell Biology/Cytoskeleton
                Microbiology/Cellular Microbiology and Pathogenesis
                Molecular Biology/Transcription Initiation and Activation

                Infectious disease & Microbiology

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