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Download The Mechanism of Autophagy Induction in Helicobacter pylori Infection
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The Mechanism of Autophagy Induction in Helicobacter pylori Infection Ik-Jung Kim, Prashant Jain, and Steven R. Blanke Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, US During infection, pathogenic bacteria often usurp existing host cell processes to remodel the host-pathogen interface. During infection of gastric epithelial cells, the human gastric pathogen, Helicobacter pylori, was recently demonstrated to induce autophagy, an ancient process that is broadly conserved among most eukaryotes as a mechanism for degrading and recycling damaged intracellular components. The vacuolating cytotoxin (VacA) was demonstrated to be both essential and sufficient for H. pylori-mediated autophagy, but the mechanism by which VacA induces autophagic signaling had not been identified. To evaluate the mechanism of VacA-dependent autophagic signaling, we examined the relationship between temporal changes that occur within VacA intoxicated cells. These studies revealed that upon entering gastric epithelial cells, VacA localizes to mitochondria and induces mitochondrial fragmentation and dysfunction within 30 min. Within 60 min, autophagosomes, as well as the activation of the microtubule associated light chain protein 3 (LC3), the autophagic marker, are evident in a VacA-dependent manner. Moreover, autophagosomeassociated mitochondria were identified, suggesting the possibility that autophagosomes are formed in response to VacA-dependent mitochondrial damage by a process called mitophagy. Consistent with this idea was the finding of significant decrease in mitochondrial mass within cells intoxicated for 4 h with VacA. The accumulation of impaired mitochondria was accompanied by a loss of cellular ATP, and a concurrent rise in cytosolic calcium levels, leading us to hypothesize that these cellular changes activate AMP-activated protein kinase (AMPK), leading ultimately to the induction of autophagy. Taken together, these findings support the model that VacAmediated mitochondrial damage is the trigger for the induction of mitophagy in an AMPK-dependent manner. This is the first example of mitophagic signaling triggered by any microbial virulence factor, and we propose that mitophagy may limit the extent of toxin-mediated mitochondrial damage.
