Toxoplasma gondii ACL and ACS - contribution to subcellular acetyl-CoA pools

Acetyl-CoA is a key metabolite in all organisms, implicated in transcriptional regulation, post-translational modification as well as fuelling the TCA-cycle and the synthesis and elongation of fatty acids (FAs). The obligate intracellular parasite Toxoplasma gondii possesses two enzymes which produce acetyl-CoA in the cytosol and nucleus: acetyl-CoA synthetase (ACS) and ATP-citrate lyase (ACL), while the branched-chain a-keto acid dehydrogenase-complex (BCKDH) generates acetyl-CoA in the mitochondrion. To obtain a global and integrative picture of the role of distinct sub-cellular acetyl-CoA pools, we measured the acetylome, transcriptome, proteome and metabolome of parasites lacking ACL/ACS or BCKDH. Loss of ACL/ACS results in the hypo-acetylation of nucleo-cytosolic and secretory proteins, alters gene expression broadly and is required for the synthesis of parasite-specific FAs. In contrast, loss of BCKDH causes few specific changes in the acetylome, transcriptome and proteome which allow these parasites to rewire their metabolism to adapt to the obstruction of the TCA-cycle.