title: Differentiation-induced uroplakin III expression promotes urothelial cell death in response to uropathogenic E. coli.
abstract: Uropathogenic E. coli (UPEC) expressing type 1 pili underlie most urinary tract infections (UTIs). UPEC adherence to the bladder urothelium induces a rapid apoptosis and exfoliation of terminally differentiated urothelial cells, a critical event in pathogenesis. Of the four major uroplakin proteins that are densely expressed on superficial urothelial cells, UPIa serves as the receptor for type 1-piliated UPEC, but the contributions of uroplakins to cell death are not known. We examined the role of differentiation and uroplakin expression on UPEC-induced cell death. Utilizing in vitro models of urothelial differentiation, we demonstrated induction of tissue-specific differentiation markers including uroplakins. UPEC-induced urothelial cell death was shown to increase with enhanced differentiation but required expression of uroplakin III: infection with an adenovirus encoding uroplakin III significantly increased cell death, while siRNA directed against uroplakin III abolished UPEC-induced cell death. In a murine model of UTI where superficial urothelial cells were selectively eroded to expose less differentiated cells, urothelial apoptosis was reduced, indicating a requirement for differentiation in UPEC-induced apoptosis in vivo. These data suggest that induction of uroplakin III during urothelial differentiation sensitizes cells to UPEC-induced death. Thus, uroplakin III plays a pivotal role in UTI pathogenesis.
authors.affiliation: Department of Urology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Thumbikat
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Berry
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Schaeffer
authors.forename: David J
authors.initials: DJ
authors.lastname: Klumpp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002460:Cell Line; D003556:Cystitis / Q000382:microbiology / Q000473:pathology*; D004926:Escherichia coli / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000382:microbiology / Q000473:pathology; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D001743:Urinary Bladder / Q000166:cytology / Q000382:microbiology; D060171:Uroplakin III; D019459:Urothelium / Q000166:cytology / Q000382:microbiology / Q000473:pathology
chemical_list: D008562:Membrane Glycoproteins; D010455:Peptides; C554660:UPK3A protein, human; C554661:Upk3a protein, mouse; D060171:Uroplakin III