Bacteria-induced uroplakin signaling mediates bladder response to infection.
Urinary tract infections are the second most common infectious disease in humans and are predominantly caused by uropathogenic E. coli (UPEC). A majority of UPEC isolates express the type 1 pilus adhesin, FimH, and cell culture and murine studies demonstrate that FimH is involved in invasion and apoptosis of urothelial cells. FimH initiates bladder pathology by binding to the uroplakin receptor complex, but the subsequent events mediating pathogenesis have not been fully characterized. We report a hitherto undiscovered signaling role for the UPIIIa protein, the only major uroplakin with a potential cytoplasmic signaling domain, in bacterial invasion and apoptosis. In response to FimH adhesin binding, the UPIIIa cytoplasmic tail undergoes phosphorylation on a specific threonine residue by casein kinase II, followed by an elevation of intracellular calcium. Pharmacological inhibition of these signaling events abrogates bacterial invasion and urothelial apoptosis in vitro and in vivo. Our studies suggest that bacteria-induced UPIIIa signaling is a critical mediator of bladder responses to insult by uropathogenic E. coli.
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Praveen
P
Thumbikat
Ruth E
RE
Berry
Ge
G
Zhou
Benjamin K
BK
Billips
Ryan E
RE
Yaggie
Tetiana
T
Zaichuk
Tung-Tien
TT
Sun
Anthony J
AJ
Schaeffer
David J
DJ
Klumpp
D018830:Adhesins, Escherichia coli / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001422:Bacterial Adhesion; D002118:Calcium / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism; D002461:Cell Line, Transformed; D004926:Escherichia coli / Q000472:pathogenicity* / Q000502:physiology; D004927:Escherichia coli Infections / Q000382:microbiology*; D029968:Escherichia coli Proteins / Q000378:metabolism; D005260:Female; D036781:Fimbriae Proteins / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D015398:Signal Transduction; D014552:Urinary Tract Infections / Q000382:microbiology*; D060171:Uroplakin III; D019459:Urothelium / Q000166:cytology / Q000378:metabolism
D018830:Adhesins, Escherichia coli; D029968:Escherichia coli Proteins; D008562:Membrane Glycoproteins; D060171:Uroplakin III; C489721:fimC protein, E coli; C058769:fimH protein, E coli; D036781:Fimbriae Proteins; D047390:Casein Kinase II; D002118:Calcium