Elongator Protein 3 (Elp3) Lysine Acetyltransferase Is a Tail-anchored Mitochondrial Protein in Toxoplasma gondii

Stilger, Krista L.; Sullivan, William J.

doi:10.1074/jbc.m113.491373

Cited by 32 publications

(43 citation statements)

References 54 publications

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“…We previously identified an unusual homologue of Elp3 as a TA membrane protein in Toxoplasma that resides at the outer membrane of the parasite’s single mitochondrion 20 . We performed a bioinformatics survey to identify other candidate TA proteins in the parasite in order to investigate targeting of this unusual protein family in an early-branching eukaryote.…”

Section: Resultsmentioning

confidence: 99%

“…RBD contains an RNA-binding domain that is likely to be involved in stabilizing RNA; its localization at the ER could signify a functional role in protein synthesis. Interestingly, RlmN contains a radical SAM domain and is a mitochondrial TA protein, like TgElp3 20 . Proteins with a radical SAM domain are associated with the delivery of diverse methylation modifications; Elp3 and RlmN in particular have been shown to have tRNA methyltransferase activity 54–56 .…”

Section: Resultsmentioning

confidence: 99%

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Targeting of tail‐anchored membrane proteins to subcellular organelles in Toxoplasma gondii

Padgett

Arrizabalaga

Sullivan

2017

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Proper protein localization is essential for critical cellular processes, including vesicle-mediated transport and protein translocation. Tail-anchored (TA) proteins are integrated into organellar membranes via the C-terminus, orienting the N-terminus towards the cytosol. Localization of TA proteins occurs post-translationally and is governed by the C-terminus, which contains the integral transmembrane domain (TMD) and targeting sequence. Targeting of TA proteins is dependent on the hydrophobicity of the TMD as well as the length and composition of flanking amino acid sequences. We previously identified an unusual homologue of elongator protein, Elp3, in the apicomplexan parasite Toxoplasma gondii as a TA protein targeting the outer mitochondrial membrane. We sought to gain further insight into TA proteins and their targeting mechanisms using this early-branching eukaryote as a model. Our bioinformatics analysis uncovered 59 predicted TA proteins in Toxoplasma, nine of which were selected for follow-up analyses based on representative features. We identified novel TA proteins that traffic to specific organelles in Toxoplasma, including the parasite endoplasmic reticulum, mitochondrion, and Golgi apparatus. Domain swap experiments elucidated that targeting of TA proteins to these specific organelles was strongly influenced by the TMD sequence, including charge of the flanking C-terminal sequence.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Targeting of tail‐anchored membrane proteins to subcellular organelles in Toxoplasma gondii

Padgett

Arrizabalaga

Sullivan

2017

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“…In addition, the Elongator protein 3 (ELP3), a GNAT-family HAT, has been shown to be tail anchored to the mitochondrial outer membrane in Toxoplasma gondii [35]. Recent result suggests that lysine acetylation also occurs nonenzymatically in mitochondria (auto-acetylation), indicating a combined operation of spontaneous lysine acetylation and enzyme-catalyzed acetylation [7,36].…”

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confidence: 98%

Histone Acetylation Enzymes Coordinate Metabolism and Gene Expression

Shen

Wei

Zhou

2015

Trends in Plant Science

229

152

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“…FR23522 and its derivatives also display potent activity against Toxoplasma by targeting a KDAC called TgHDAC3 (4,5). In contrast, there are no reports to date of a Toxoplasma KAT inhibitor despite genetic studies showing that KATs are essential for parasite viability (6)(7)(8)(9)(10)(11)(12)(13). The putative KAT inhibitor MC1626 has inhibitory activity against tachyzoites but most likely through an off-target effect (14).…”

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Garcinol Inhibits GCN5-Mediated Lysine Acetyltransferase Activity and Prevents Replication of the Parasite Toxoplasma gondii

Jeffers

Gao

Checkley

et al. 2016

Antimicrob Agents Chemother

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Lysine acetylation is a critical posttranslational modification that influences protein activity, stability, and binding properties. The acetylation of histone proteins in particular is a well-characterized feature of gene expression regulation. In the protozoan parasite Toxoplasma gondii, a number of lysine acetyltransferases (KATs) contribute to gene expression and are essential for parasite viability. The natural product garcinol was recently reported to inhibit enzymatic activities of GCN5 and p300 family KATs in other species. Here we show that garcinol inhibits TgGCN5b, the only nuclear GCN5 family KAT known to be required for Toxoplasma tachyzoite replication. Treatment of tachyzoites with garcinol led to a reduction of global lysine acetylation, particularly on histone H3 and TgGCN5b itself. We also performed transcriptome sequencing (RNA-seq), which revealed increasing aberrant gene expression coincident with increasing concentrations of garcinol. The majority of the genes that were most significantly affected by garcinol were also associated with TgGCN5b in a previously reported chromatin immunoprecipitation assay with microarray technology (ChIP-chip) analysis. The dysregulated gene expression induced by garcinol significantly inhibits Toxoplasma tachyzoite replication, and the concentrations used exhibit no overt toxicity on human host cells. Garcinol also inhibits Plasmodium falciparum asexual replication with a 50% inhibitory concentration (IC 50 ) similar to that for Toxoplasma. Together, these data support that pharmacological inhibition of TgGCN5b leads to a catastrophic failure in gene expression control that prevents parasite replication.

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Elongator Protein 3 (Elp3) Lysine Acetyltransferase Is a Tail-anchored Mitochondrial Protein in Toxoplasma gondii

Cited by 32 publications

References 54 publications

Targeting of tail‐anchored membrane proteins to subcellular organelles in Toxoplasma gondii

Targeting of tail‐anchored membrane proteins to subcellular organelles in Toxoplasma gondii

Histone Acetylation Enzymes Coordinate Metabolism and Gene Expression

Garcinol Inhibits GCN5-Mediated Lysine Acetyltransferase Activity and Prevents Replication of the Parasite Toxoplasma gondii

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