The anti-tubercular activity of simvastatin is mediated by cholesterol-dependent regulation of autophagy via the AMPK-mTORC1-TFEB axis
| Autor: | Petros C. Karakousis, Valentina Guerrini, Maria Laura Gennaro, Noton K. Dutta, Ken D. Yamaguchi, Hugh Salamon, Natalie Bruiners |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Chemistry Autophagy AMPK mTORC1 Pharmacology 3. Good health 03 medical and health sciences 0302 clinical medicine Simvastatin 030220 oncology & carcinogenesis medicine Protein prenylation TFEB lipids (amino acids peptides and proteins) Mevalonate pathway Protein kinase A 030304 developmental biology medicine.drug |
| DOI: | 10.1101/2020.03.04.977579 |
| Popis: | Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. We investigated the mechanism of anti-tubercular action of simvastatin in Mycobacterium tuberculosis-infected human monocytic cells. We found that the anti-tubercular activity of statins was phenocopied by cholesterol-branch but not prenylation-branch inhibitors. Moreover, statin treatment blocked activation of mechanistic target of rapamycin complex 1 (mTORC1), activated AMP-activated protein kinase (AMPK) through increased intracellular AMP:ATP ratios, and favored nuclear translocation of transcription factor EB (TFEB). These mechanisms all induce autophagy, which is anti-mycobacterial. The biological effects of simvastatin on the AMPK-mTORC1-TFEB-autophagy axis were reversed by adding exogenous cholesterol to the cells. Overall, our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, AMPK-mTORC1-TFEB axis, and intracellular infection control, and uncover new anti-tubercular therapy targets. |
| Databáze: | OpenAIRE |
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