Shigella Effector IpaH9.8 Interacts with Autophagy Transcription Factor ZKSCAN3 and Increases Autophagy During Infection

Abstract

Shigella spp. cause severe diarrheal disease known as shigellosis and are a major problem is countries where clean water and sanitation are lacking. Shigella spp. use a Type 3 Secretion System to deliver effector proteins into the cytosol of infected human cells. My thesis focuses on an effector of Shigella flexneri, IpaH9.8, and its role in pathogenesis. IpaH9.8 is a member of a structurally related family of enzymes called the novel E3 ligases (NELs). NEL-domain proteins are E3 ubiquitin ligases that target host proteins to alter their fate. I show that IpaH9.8 ubiquitinates ZKSCAN3, a negative regulator of genes required for autophagy, in a cell free system and induces autophagy in vitro. My results are consistent with a model where S. flexneri uses IpaH9.8 to induce autophagy resulting in degradation of host proteins to produce free amino acids and down-regulate the activity of immune complexes.