Shigella Effector IpaH9.8 Modulates a Host Ubiquitin-Like Pathway and Lysosomal Biogenesis

Abstract

The bacterium Shigella causes bacterial dysentery in developing countries and represents a persistent burden to healthcare systems due to an increase in antibiotic-resistant strains and lack of a vaccine strategy. Shigella encodes a type III secretion system to inject effector proteins into the eukaryotic cytosol to hijack and disrupt host processes. One of these effectors is IpaH9.8, a Novel E3 ubiquitin Ligase (NEL) that can target host proteins for post-translational modification with ubiquitin. Cellular targets for IpaH9.8 are unknown despite more than a decade of searching. My results are consistent with a model where IpaH9.8 interacts with a ubiquitin-like protein, UFM1. By co- immunoprecipitation, mass spectrometry, and in vitro UFMylation I have identified Galectin-7, a sugar-binding protein, as an IpaH9.8 target. Additionally, I have characterized another IpaH9.8 interactor, ZKSCAN3, a negative regulator of lysosomal biogenesis, and have provided preliminary evidence that Shigella manipulate host lysosomes through ubiquitination of ZKSCAN3.