Editors' ChoiceHost-Microbe Interactions

Bacterial manipulation of host cell metabolism

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Sci. Signal.  29 May 2018:
Vol. 11, Issue 532, eaau2601
DOI: 10.1126/scisignal.aau2601

A Helicobacter pylori exotoxin manipulates host cell metabolism by inducing amino acid starvation and inhibiting mTORC1 signaling.

Helicobacter pylori infection is associated with increased susceptibility to developing gastric ulcers and cancers. The vacuolating cytotoxin VacA is an H. pylori exotoxin that enters cells and forms channels on intracellular membranes, stimulating vacuole biogenesis, autophagy, and mitochondrial dysfunction. Kim et al. found that H. pylori infection or exposure to factors secreted by H. pylori inhibited mechanistic target of rapamycin complex 1 (mTORC1) signaling in HEK293T cells in a manner that depended on the H. pylori strain having a functional vacA allele. Purified VacA inhibited mTORC1 signaling and stimulated autophagy in several human gastric and duodenal cell lines, primary murine gastric epithelial cells, and murine gastric tissue slices. Under nutrient-replete conditions, mTORC1 is recruited to lysosomal membranes, where it becomes activated, and suppresses autophagy by inhibiting the kinase Ulk1; however, when nutrients are limiting, mTORC1 is not recruited to lysosomes, and its signaling activity is inhibited, leading to Ulk1-mediated induction of autophagy. Treating cells with VacA depleted intracellular amino acids, which caused mTORC1 to dissociate from lysosomal membranes, thus stimulating Ulk1 activation. VacA did not reduce mTORC1 signaling when mTORC1 was prevented from dissociating from lysosomal membranes or when VacA lacked the N-terminal domain that targets it to mitochondria. Preventing VacA-induced mitochondrial fragmentation blocked the VacA-dependent inhibition of mTORC1 signaling and stimulation of autophagy. The precise mechanism by which VacA reduced intracellular amino acids was not discovered, but these results demonstrate that this H. pylori toxin fundamentally changes the metabolic state of host cells by effectively inducing amino acid starvation.

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