PLoS Pathogens | |
Bacterial and Host Determinants of MAL Activation upon EPEC Infection: The Roles of Tir, ABRA, and FLRT3 | |
Ramnik J. Xavier1  Laura M. Machesky1  Robert J. W. Heath2  Balázs Visegrády3  John M. Leong4  | |
[1] Beatson Institute for Cancer Research, Garscube Estate, Bearsden, Glasgow, United Kingdom;Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America;Department of Molecular Genetics and Microbiology, UMass Medical School, Worcester, Massachusetts, United States of America;Gastrointestinal Unit, Center for Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America | |
关键词: Actins; Host cells; Small interfering RNAs; Transcription factors; Cytoskeleton; Bacterial pathogens; DNA transcription; Secretion systems; | |
DOI : 10.1371/journal.ppat.1001332 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
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【 摘 要 】
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.
【 授权许可】
CC BY
【 预 览 】
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