Pore-Forming Pathogens Activate the Inflammasome

Abstract

Pathogenic microbes introduce pores in the host plasma membrane as part of the infectious process. Gurcel et al . determined that pore-forming toxins, such as aerolysin from Aeromonas and α-toxin from Staphylococcus aureus , stimulate the SREBP (sterol response element–binding protein) transcription factors to promote membrane repair. RNA differential display analysis suggested that aerolysin increased the expression of the gene encoding SREBP-2. Indeed, exposure of cells to either aerolysin or α-toxin increased the activity of SREBP-2. In Chinese hamster ovary cells, exposure to aerolysin stimulated proteolytic processing of SREBP-1 and SREBP-2 to release these membrane-bound transcription factors from the endoplasmic reticulum and allowed translocation to the nucleus of the transcriptionally active fragment. The increase in the activity of the SREBPs was verified by an increase in the expression of target genes and an increase in total cellular cholesterol through both increased biosynthesis and uptake (the low-density lipoprotein receptor is encoded by a SREBP-responsive gene). Mutant aerolysin subunits that could not form pores were incapable of stimulating SREBP-2 activity, and SREBP-2 activation required K + efflux but did not require an increase in intracellular calcium concentration. Indeed, exposure of cells to a K + , but not a Na + , ionophore, triggered SREBP-2 activation. Decreased intracellular K + concentration is known to activate caspase 1 through activation of inflammasomes with either the IPAF or NALP3 subunits, which are intracellular pattern recognition receptors. When RNA interference was used to knock down subunits of the IPAF or NALP3 inflammasome, the activation of caspase 1 and SREBP-2 in response to aerolysin was diminished. Pharmacological inhibition or knockdown of caspase 1 also prevented SREBP-2 activation. SREBP-2 was not directly cleaved by caspase 1; instead, caspase 1 activated the known SREBP-activating pathway that involves SCAP (an escort protein) and S1P and S2P (the two enzymes responsible for SREBP proteolysis and release). Using various pharmacological and RNAi approaches, the authors showed that activation of the inflammasome caspase 1 and the SREBPs was required for cell survival after exposure to aerolysin. Saleh discusses these findings. L. Gurcel, L. Abrami, S. Girardin, J. Tschopp, F. G. van der Goot, Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell 126 , 1135-1145 (2006). [Online Journal] M. Saleh, Caspase-1 builds a new barrier to infection. Cell 126 , 1028-1030 (2006). [Online Journal]