Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program.
Autophagy, which targets cellular constituents for degradation, is normally inhibited in metabolically replete cells by the metabolic checkpoint kinase mTOR. Although autophagic degradation of invasive bacteria has emerged as a critical host defense mechanism, the signals that induce autophagy upon bacterial infection remain unclear. We find that infection of epithelial cells with Shigella and Salmonella triggers acute intracellular amino acid (AA) starvation due to host membrane damage. Pathogen-induced AA starvation caused downregulation of mTOR activity, resulting in the induction of autophagy. In Salmonella-infected cells, membrane integrity and cytosolic AA levels rapidly normalized, favoring mTOR reactivation at the surface of the Salmonella-containing vacuole and bacterial escape from autophagy. In addition, bacteria-induced AA starvation activated the GCN2 kinase, eukaryotic initiation factor 2α, and the transcription factor ATF3-dependent integrated stress response and transcriptional reprogramming. Thus, AA starvation induced by bacterial pathogens is sensed by the host to trigger protective innate immune and stress responses.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
Ivan
I
Tattoli
Matthew T
MT
Sorbara
Dajana
D
Vuckovic
Arthur
A
Ling
Fraser
F
Soares
Leticia A M
LA
Carneiro
Chloe
C
Yang
Andrew
A
Emili
Dana J
DJ
Philpott
Stephen E
SE
Girardin
D000596:Amino Acids / Q000378:metabolism*; D001343:Autophagy; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D012475:Salmonella / Q000276:immunology* / Q000472:pathogenicity; D012760:Shigella / Q000276:immunology* / Q000472:pathogenicity; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis
D000596:Amino Acids; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases