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 Robert Blanke

Research output: Contribution to journalArticle

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

Fingerprint

Helicobacter Infections
Helicobacter pylori
Autophagy
Amino Acids
Mitochondria
Bacterial Toxins
Exotoxins
Cytotoxins
Nutritional Status
mechanistic target of rapamycin complex 1
Homeostasis
Food
Infection

Keywords

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

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

Cite this

Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1. / Kim, Ik Jung; Lee, Jeongmin; Oh, Seung J.; Yoon, Mee Sup; Jang, Sung Soo; Holland, Robin L.; Reno, Michael L.; Hamad, Mohammed N.; Maeda, Tatsuya; Chung, Hee Jung; Chen, Jie; Blanke, Steven Robert.

In: Cell Host and Microbe, Vol. 23, No. 5, 09.05.2018, p. 583-593.e8.

Research output: Contribution to journalArticle

Kim, IJ, Lee, J, Oh, SJ, Yoon, MS, Jang, SS, Holland, RL, Reno, ML, Hamad, MN, Maeda, T, Chung, HJ, Chen, J & Blanke, SR 2018, 'Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1' Cell Host and Microbe, vol. 23, no. 5, pp. 583-593.e8. https://doi.org/10.1016/j.chom.2018.04.006
Kim, Ik Jung ; Lee, Jeongmin ; Oh, Seung J. ; Yoon, Mee Sup ; Jang, Sung Soo ; Holland, Robin L. ; Reno, Michael L. ; Hamad, Mohammed N. ; Maeda, Tatsuya ; Chung, Hee Jung ; Chen, Jie ; Blanke, Steven Robert. / Helicobacter pylori Infection Modulates Host Cell Metabolism through VacA-Dependent Inhibition of mTORC1. In: Cell Host and Microbe. 2018 ; Vol. 23, No. 5. pp. 583-593.e8.
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