A TRP Channel Senses Lysosome Neutralization by Pathogens to Trigger Their Expulsion

Vertebrate cells have evolved elaborate cell-autonomous defense programs to monitor subcellular compartments for infection and to evoke counter-responses. These programs are activated by pathogen-associated pattern molecules and by various strategies intracellular pathogens employ to alter cellular microenvironments. Here, we show that, when uropathogenic E. coli (UPEC) infect bladder epithelial cells (BECs), they are targeted by autophagy but avoid degradation because of their capacity to neutralize lysosomal pH. This change is detected by mucolipin TRP channel 3 (TRPML3), a transient receptor potential cation channel localized to lysosomes. TRPML3 activation then spontaneously initiates lysosome exocytosis, resulting in expulsion of exosome-encased bacteria. These studies reveal a cellular default system for lysosome homeostasis that has been co-opted by the autonomous defense program to clear recalcitrant pathogens. [Display omitted] •Intracellular UPEC are encased in exosomes when expelled from BECs•UPEC are delivered from autophagosome into MVB, eventually reaching lysosomes•Neutralization of bacteria-bearing lysosomes induces lysosome exocytosis•TRPML3 senses neutralized lysosomal pH and triggers Ca2+ efflux Non-lytic expulsion of bacteria from infected cells is a powerful cell-autonomous defense strategy to rapidly reduce infection burden in the bladder. The expulsion from infected BECs is triggered by TRPML3. This lysosomal TRP channel senses the UPEC-mediated lysosome neutralization and releases Ca2+, triggering lysosome exocytosis to expel the bacteria.