Pro-autophagic signal induction by bacterial pore-forming toxins.
Pore-forming toxins (PFT) comprise a large, structurally heterogeneous group of bacterial protein toxins. Nucleated target cells mount complex responses which allow them to survive moderate membrane damage by PFT. Autophagy has recently been implicated in responses to various PFT, but how this process is triggered is not known, and the significance of the phenomenon is not understood. Here, we show that S. aureus α-toxin, Vibrio cholerae cytolysin, streptolysin O and E. coli haemolysin activate two pathways leading to autophagy. The first pathway is triggered via AMP-activated protein kinase (AMPK). AMPK is a major energy sensor which induces autophagy by inhibiting the target of rapamycin complex 1 (TORC1) in response to a drop of the cellular ATP/AMP-ratio, as is also observed in response to membrane perforation. The second pathway is activated by the conserved eIF2α-kinase GCN2, which causes global translational arrest and promotes autophagy in response to starvation. The latter could be accounted for by impaired amino acid transport into target cells. Notably, PKR, an eIF2α-kinase which has been implicated in autophagy induction during viral infection, was also activated upon membrane perforation, and evidence was obtained that phosphorylation of eIF2α is required for the accumulation of autophagosomes in α-toxin-treated cells. Treatment with 3-methyl-adenine inhibited autophagy and disrupted the ability of cells to recover from sublethal attack by S. aureus α-toxin. We propose that PFT induce pro-autophagic signals through membrane perforation-dependent nutrient and energy depletion, and that an important function of autophagy in this context is to maintain metabolic homoeostasis.
Kloft
Nicole
N
Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
Neukirch
Claudia
C
Bobkiewicz
Wiesia
W
Veerachato
Gunnaporn
G
Busch
Tim
T
von Hoven
Gisela
G
Boller
Klaus
K
Husmann
Matthias
M
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001427:Bacterial Toxins / Q000633:toxicity*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
D001427:Bacterial Toxins; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
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