Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival.
Many pathogenic organisms produce pore-forming toxins as virulence factors. Target cells however mount a response to such membrane damage. Here we show that toxin-induced membrane permeabilization leads to a decrease in cytoplasmic potassium, which promotes the formation of a multiprotein oligomeric innate immune complex, called the inflammasome, and the activation of caspase-1. Further, we find that when rendered proteolytic in this context caspase-1 induces the activation of the central regulators of membrane biogenesis, the Sterol Regulatory Element Binding Proteins (SREBPs), which in turn promote cell survival upon toxin challenge possibly by facilitating membrane repair. This study highlights that, in addition to its well-established role in triggering inflammation via the processing of the precursor forms of interleukins, caspase-1 has a broader role, in particular linking the intracellular ion composition to lipid metabolic pathways, membrane biogenesis, and survival.
Gurcel
Laure
L
Department Microbiology and Molecular Medicine, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland.
Abrami
Laurence
L
Girardin
Stephen
S
Tschopp
Jurg
J
van der Goot
F Gisou
FG
D000333:Aeromonas / Q000378:metabolism; D000818:Animals; D001424:Bacterial Infections / Q000378:metabolism / Q000503:physiopathology; D001427:Bacterial Toxins / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D020170:Caspase 1 / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D006224:Cricetinae; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D008563:Membrane Lipids / Q000378:metabolism*; D052899:Pore Forming Cytotoxic Proteins; D011188:Potassium / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*
D001427:Bacterial Toxins; D008563:Membrane Lipids; D052899:Pore Forming Cytotoxic Proteins; D051782:Sterol Regulatory Element Binding Protein 2; D051779:Sterol Regulatory Element Binding Proteins; C032676:aerolysin; D020170:Caspase 1; D011188:Potassium