Journal
BMC BIOLOGY
Volume 18, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12915-020-00791-7
Keywords
Toxoplasma gondii; Acetyl-CoA; Branched-chain alpha-keto acid dehydrogenase-complex (BCKDH); ATP citrate lyase (ACL); Acetyl-CoA synthetase (ACS); Acetylome; Multi-omics; Metabolism; Phosphoenolpyruvate carboxykinase (PEPCK); Formate/nitrite transporter (FNT)
Categories
Funding
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [695596]
- Agence Nationale de la Recherche [ANR-10-INBS-08-01 ProFI, ANR-12-BSV3-0009 TOXOHDAC]
- LabEx ParaFrap [ANR-11-LABX-0024]
- ERC [614880 Hosting TOXO]
- iGE3 program from the University of Geneva
- SNSF [CRSII3_160702, 51PHP0_157303]
- Swiss National Science Foundation (SNF) [CRSII3_160702] Funding Source: Swiss National Science Foundation (SNF)
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Background Acetyl-CoA is a key molecule in all organisms, implicated in several metabolic pathways as well as in transcriptional regulation and post-translational modification. The human pathogenToxoplasma gondiipossesses at least four enzymes which generate acetyl-CoA in the nucleo-cytosol (acetyl-CoA synthetase (ACS); ATP citrate lyase (ACL)), mitochondrion (branched-chain alpha-keto acid dehydrogenase-complex (BCKDH)) and apicoplast (pyruvate dehydrogenase complex (PDH)). Given the diverse functions of acetyl-CoA, we know very little about the role of sub-cellular acetyl-CoA pools in parasite physiology. Results To assess the importance and functions of sub-cellular acetyl-CoA-pools, we measured the acetylome, transcriptome, proteome and metabolome of parasites lacking ACL/ACS or BCKDH. We demonstrate that ACL/ACS constitute a synthetic lethal pair. Loss of both enzymes causes a halt in fatty acid elongation, hypo-acetylation of nucleo-cytosolic and secretory proteins and broad changes in gene expression. In contrast, loss of BCKDH results in an altered TCA cycle, hypo-acetylation of mitochondrial proteins and few specific changes in gene expression. We provide evidence that changes in the acetylome, transcriptome and proteome of cells lacking BCKDH enable the metabolic adaptations and thus the survival of these parasites. Conclusions Using multi-omics and molecular tools, we obtain a global and integrative picture of the role of distinct acetyl-CoA pools inT. gondiiphysiology. Cytosolic acetyl-CoA is essential and is required for the synthesis of parasite-specific fatty acids. In contrast, loss of mitochondrial acetyl-CoA can be compensated for through metabolic adaptations implemented at the transcriptional, translational and post-translational level.
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