Feel the Burn, then Feel the Death. ExoU as a Phospholipase

Abstract

A major cause of infection‐related deaths in immunocompromised patients is the protein toxin ExoU, encoded by the bacterium Pseudomonas aeruginosa. The Brown Deer SMART (Students Modeling A Research Topic) Team has modeled ExoU using 3D printing technology to have a better grasp on how the toxin interacts with eukaryotic cells. P. aeruginosa uses a type 3 secretion system (T3SS) to inject toxins including ExoU into the cell to disrupt its functionality. The T3SS is a needle‐like structure comprised of proteins that allow the bacterium to transfer effector proteins into innate immune cells. ExoU travels through the T3SS using a chaperone protein (SpcU). Once inside the eukaryotic cell, ExoU interacts with ubiquitin, where it refolds into an active potent phospholipase that breaks down cellular membranes using Ser142 and Asp344 as the catalytic amino acids. The exact mechanism is unknown but the C‐terminus (residues 580–683) helps in targeting the membrane, allowing ExoU to break it down. P. aeruginosa is able to freely reproduce inside the environment of the host organism as the immune system is not able to compensate for the infected cells and bacterium. Left unchecked, this infection will prove fatal. Research is being conducted to create an ExoU inhibitor to reduce the deaths it causes in patients with compromised immune systems. Supported by a grant from NIH‐CTSA UL1RR031973.