title: The UPEC pore-forming toxin α-hemolysin triggers proteolysis of host proteins to disrupt cell adhesion, inflammatory, and survival pathways.
abstract: Uropathogenic Escherichia coli (UPEC), which are the leading cause of both acute and chronic urinary tract infections, often secrete a labile pore-forming toxin known as α-hemolysin (HlyA). We show that stable insertion of HlyA into epithelial cell and macrophage membranes triggers degradation of the cytoskeletal scaffolding protein paxillin and other host regulatory proteins, as well as components of the proinflammatory NFκB signaling cascade. Proteolysis of these factors requires host serine proteases, and paxillin degradation specifically involves the serine protease mesotrypsin. The induced activation of mesotrypsin by HlyA is preceded by redistribution of mesotrypsin precursors from the cytosol into foci along microtubules and within nuclei. HlyA intoxication also stimulated caspase activation, which occurred independently of effects on host serine proteases. HlyA-induced proteolysis of host proteins likely allows UPEC to not only modulate epithelial cell functions, but also disable macrophages and suppress inflammatory responses.
authors.affiliation: Division of Microbiology and Immunology, Pathology Department, University of Utah School of Medicine, Salt Lake City, Utah 84112-0565, USA.
authors.forename: Bijaya K
authors.initials: BK
authors.lastname: Dhakal
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Mulvey
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000378:metabolism / Q000633:toxicity*; D006460:Hemolysin Proteins / Q000378:metabolism / Q000633:toxicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D051419:Paxillin / Q000378:metabolism; D059748:Proteolysis; D057057:Serine Proteases / Q000378:metabolism*; D015398:Signal Transduction; D056689:Uropathogenic Escherichia coli / Q000472:pathogenicity*
chemical_list: D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; D051419:Paxillin; D057057:Serine Proteases