Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1

Ik Jung Kim, Jeongmin Lee, Seung J. Oh, Mee Sup Yoon, Sung Soo Jang, Robin L. Holland, Michael L. Reno, Mohammed N. Hamad, Tatsuya Maeda, Hee Jung Chung, Jie Chen, Steven R. Blanke

Research output: Contribution to journalArticlepeer-review

Abstract

Helicobacter pylori (Hp) vacuolating cytotoxin (VacA) is a bacterial exotoxin that enters host cells and induces mitochondrial dysfunction. However, the extent to which VacA-dependent mitochondrial perturbations affect overall cellular metabolism is poorly understood. We report that VacA perturbations in mitochondria are linked to alterations in cellular amino acid homeostasis, which results in the inhibition of mammalian target of rapamycin complex 1 (mTORC1) and subsequent autophagy. mTORC1, which regulates cellular metabolism during nutrient stress, is inhibited during Hp infection by a VacA-dependent mechanism. This VacA-dependent inhibition of mTORC1 signaling is linked to the dissociation of mTORC1 from the lysosomal surface and results in activation of cellular autophagy through the Unc 51-like kinase 1 (Ulk1) complex. VacA intoxication results in reduced cellular amino acids, and bolstering amino acid pools prevents VacA-mediated mTORC1 inhibition. Overall, these studies support a model that Hp modulate host cell metabolism through the action of VacA at mitochondria. Dysregulation of host metabolism is emerging as an important strategy for microbial remodeling of the infection microenvironment. Kim et al. report a key sensor of host nutritional status, mTORC1, is inhibited by a mitochondrial-targeting bacterial toxin, Helicobacter pylori VacA, resulting in an overall cellular shift from biosynthetic to catabolic metabolism.

Original languageEnglish (US)
Pages (from-to)583-593.e8
JournalCell Host and Microbe
Volume23
Issue number5
DOIs
StatePublished - May 9 2018

Keywords

  • Helicobacter pylori
  • Ulk 1
  • VacA
  • amino acid homeostasis
  • autophagy
  • mTOR
  • mTORC1
  • metabolism
  • mitochondria
  • mitochondrial dysfunction
  • vacuolating cytotoxin

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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