The type III effector EspF coordinates membrane trafficking by the spatiotemporal activation of two eukaryotic signaling pathways.
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.
Alto
Neal M
NM
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
Weflen
Andrew W
AW
Rardin
Matthew J
MJ
Yarar
Defne
D
Lazar
Cheri S
CS
Tonikian
Raffi
R
Koller
Antonius
A
Taylor
Susan S
SS
Boone
Charles
C
Sidhu
Sachdev S
SS
Schmid
Sandra L
SL
Hecht
Gail A
GA
Dixon
Jack E
JE
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
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