title: The type III effector EspF coordinates membrane trafficking by the spatiotemporal activation of two eukaryotic signaling pathways.
abstract: Bacterial toxins and effector proteins hijack eukaryotic enzymes that are spatially localized and display rapid signaling kinetics. However, the molecular mechanisms by which virulence factors engage highly dynamic substrates in the host cell environment are poorly understood. Here, we demonstrate that the enteropathogenic Escherichia coli (EPEC) type III effector protein EspF nucleates a multiprotein signaling complex composed of eukaryotic sorting nexin 9 (SNX9) and neuronal Wiskott-Aldrich syndrome protein (N-WASP). We demonstrate that a specific and high affinity association between EspF and SNX9 induces membrane remodeling in host cells. These membrane-remodeling events are directly coupled to N-WASP/Arp2/3-mediated actin nucleation. In addition to providing a biochemical mechanism of EspF function, we find that EspF dynamically localizes to membrane-trafficking organelles in a spatiotemporal pattern that correlates with SNX9 and N-WASP activity in living cells. Thus, our findings suggest that the EspF-dependent assembly of SNX9 and N-WASP represents a novel form of signaling mimicry used to promote EPEC pathogenesis and gastrointestinal disease.
authors: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Neal M
authors: NM
authors: Alto
authors: Andrew W
authors: AW
authors: Weflen
authors: Matthew J
authors: MJ
authors: Rardin
authors: Defne
authors: D
authors: Yarar
authors: Cheri S
authors: CS
authors: Lazar
authors: Raffi
authors: R
authors: Tonikian
authors: Antonius
authors: A
authors: Koller
authors: Susan S
authors: SS
authors: Taylor
authors: Charles
authors: C
authors: Boone
authors: Sachdev S
authors: SS
authors: Sidhu
authors: Sandra L
authors: SL
authors: Schmid
authors: Gail A
authors: GA
authors: Hecht
authors: Jack E
authors: JE
authors: Dixon
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D016764:Cell Polarity; D002470:Cell Survival; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology; D004926:Escherichia coli / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000378:metabolism*; D019143:Evolution, Molecular; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000378:metabolism; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D002352:Carrier Proteins; D029968:Escherichia coli Proteins; C489109:EspFU protein, E coli; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D033921:Vesicular Transport Proteins; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal