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Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin.
- Source :
-
Scientific reports [Sci Rep] 2017 Dec 06; Vol. 7 (1), pp. 17050. Date of Electronic Publication: 2017 Dec 06. - Publication Year :
- 2017
-
Abstract
- Animal health depends on the ability of immune cells to kill invading pathogens, and on the resilience of tissues to tolerate the presence of pathogens. Trueperella pyogenes causes tissue pathology in many mammals by secreting a cholesterol-dependent cytolysin, pyolysin (PLO), which targets stromal cells. Cellular cholesterol is derived from squalene, which is synthesized via the mevalonate pathway enzymes, including HMGCR, FDPS and FDFT1. The present study tested the hypothesis that inhibiting enzymes in the mevalonate pathway to reduce cellular cholesterol increases the resilience of stromal cells to PLO. We first verified that depleting cellular cholesterol with methyl-β-cyclodextrin increased the resilience of stromal cells to PLO. We then used siRNA to deplete mevalonate pathway enzyme gene expression, and used pharmaceutical inhibitors, atorvastatin, alendronate or zaragozic acid to inhibit the activity of HMGCR, FDPS and FDFT1, respectively. These approaches successfully reduced cellular cholesterol abundance, but mevalonate pathway enzymes did not affect cellular resilience equally. Inhibiting FDFT1 was most effective, with zaragozic acid reducing the impact of PLO on cell viability. The present study provides evidence that inhibiting FDFT1 increases stromal cell resilience to a cholesterol-dependent cytolysin.
- Subjects :
- Animals
Bacterial Proteins genetics
Bacterial Proteins pharmacology
Bacterial Toxins genetics
Bacterial Toxins pharmacology
Cattle
Cell Survival drug effects
Cholesterol analysis
Farnesyl-Diphosphate Farnesyltransferase antagonists & inhibitors
Farnesyl-Diphosphate Farnesyltransferase genetics
Farnesyl-Diphosphate Farnesyltransferase metabolism
Geranyltranstransferase antagonists & inhibitors
Geranyltranstransferase genetics
Geranyltranstransferase metabolism
Hemolysin Proteins genetics
Hemolysin Proteins pharmacology
Humans
Hydroxymethylglutaryl CoA Reductases chemistry
Hydroxymethylglutaryl CoA Reductases genetics
Hydroxymethylglutaryl CoA Reductases metabolism
RNA Interference
RNA, Small Interfering metabolism
Recombinant Proteins biosynthesis
Recombinant Proteins isolation & purification
Recombinant Proteins pharmacology
Stromal Cells cytology
Stromal Cells drug effects
Stromal Cells metabolism
beta-Cyclodextrins pharmacology
Bacterial Proteins metabolism
Bacterial Toxins metabolism
Cholesterol metabolism
Hemolysin Proteins metabolism
Mevalonic Acid metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 29213055
- Full Text :
- https://doi.org/10.1038/s41598-017-17138-y