Bacteria-induced uroplakin signaling mediates bladder response to infection

• Published in: PLoS pathogens Vol. 5; no. 5; p. e1000415
• Main Authors: Thumbikat, Praveen, Berry, Ruth E, Zhou, Ge, Billips, Benjamin K, Yaggie, Ryan E, Zaichuk, Tetiana, Sun, Tung-Tien, Schaeffer, Anthony J, Klumpp, David J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-05-2009; Public Library of Science (PLoS)
• Subjects: Adhesins, Escherichia coli - metabolism; Animals; Apoptosis; Bacterial Adhesion; Calcium - metabolism; Casein Kinase II - metabolism; Causes of; Cell Biology/Cell Signaling; Cell Biology/Membranes and Sorting; Cell Line, Transformed; Cellular signal transduction; Diagnosis; Escherichia coli; Escherichia coli - pathogenicity; Escherichia coli - physiology; Escherichia coli Infections - microbiology; Escherichia coli Proteins - metabolism; Female; Fimbriae Proteins - metabolism; Health aspects; Humans; Infections; Infectious Diseases/Bacterial Infections; Infectious Diseases/Urological Infections; Kinases; Membrane Glycoproteins - metabolism; Membrane proteins; Mice; Mice, Inbred C57BL; Microbiology/Cellular Microbiology and Pathogenesis; Phosphorylation; Physiological aspects; Proteins; Signal Transduction; Urinary tract infections; Urinary Tract Infections - microbiology; Urology/Urological Infections; Uroplakin III; Urothelium - cytology; Urothelium - metabolism; United States; Fimbriae Proteins; Phosphorylation; Casein Kinase II; Calcium; Signal Transduction; Adhesins, Escherichia coli; Escherichia coli; Humans; Mice, Inbred C57BL; Bacterial Adhesion; Animals; Escherichia coli Proteins; Urinary Tract Infections; Escherichia coli Infections; Female; Mice; Membrane Glycoproteins; Uroplakin III; Cell Line, Transformed; Apoptosis; Urothelium
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1000415

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.