Protein Lactylation Critically Regulates Energy Metabolism in the Protozoan Parasite Trypanosoma brucei

Zhang, Naiwen; Jiang, Ning; Yu, Li-Ying; Guan, Tiandong; Sang, Xiaoyu; Feng, Ying; Chen, Ran; Chen, Qijun

doi:10.3389/fcell.2021.719720

Cited by 30 publications

(44 citation statements)

References 70 publications

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“…Our studies revealed that lactylated proteins were distributed in diverse compartments (especially the mitochondria) and were significantly enriched in energy metabolism processes such as oxidative phosphorylation, glyoxylate and dicarboxylate metabolism, glycolysis/gluconeogenesis, and TCA cycle (Figure 2, Figure S2 and S3). Our results are also in line with previous findings in Trypanosoma brucei and rice, where lactylation is important for gene transcription and central carbon metabolism [48,49]. We therefore focused on the link between lactylation and the processes of energy metabolism.…”

Section: Discussionsupporting

confidence: 91%

Protein Lactylation and Metabolic Regulation of the Zoonotic Parasite Toxoplasma gondii

Yin

Jiang

Cheng

et al. 2022

Preprint

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The biology of Toxoplasma gondii, the causative pathogen of one of the most wide-spread parasitic diseases remains poorly understood. Lactate, which is derived from glucose metabolic pathways, is considered to be not only an energy source in a variety of organisms including Toxoplasma gondii, but also a regulatory molecule that participates in gene activation and protein functioning. Lysine lactylation is a type of posttranslational modifications (PTMs) that was recently associated with chromatin remodeling, but lysine lactylation of histone and non-histone proteins has not yet been studied in T. gondii. To examine the prevalence and function of lactylation in T. gondii parasites, we mapped the lactylome of proliferating tachyzoite cells and found 1964 lactylation sites on 955 proteins in the T. gondii RH strain. The lactylated proteins were distributed in multiple subcellular compartments and were closely related to a wide variety of biological processes, including mRNA splicing, glycolysis, aminoacyl-tRNA biosynthesis, RNA transport, and multiple signaling pathways. We also performed chromatin immunoprecipitation sequencing (ChIP-seq) analysis with a lactylation specific antibody, the results revealed that histone H4K12la and H3K14la were enriched in the promoter and exon regions of Toxoplasma gondii genes associated with microtubule-based movement and cell invasion. We further confirmed the de-lactylase activity of histone deacetylase TgHDACs 2, 3, and 4, and that treatment with anti-histone acetyltransferase (TgMYST-A) antibodies profoundly reduced protein lactylation in the parasites. This study offers the first dataset of the global lactylation proteome and provides a basis for further dissection of the functional biology of Toxoplasma gondii.

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Section: Discussionsupporting

confidence: 91%

Protein Lactylation and Metabolic Regulation of the Zoonotic Parasite Toxoplasma gondii

Yin

Jiang

Cheng

et al. 2022

Preprint

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“…Histone sites modified through lactylation have previously been identified in several eukaryotic species [ 3 , 5 – 8 ] and were found to directly activate gene expression [ 3 ]. In the present study, a total of 20 Kla sites on T. gondii canonical and variant histones were identified, including five sites on H2B (K37, K47, K70, K77 and K99), four sites on H3 (K23, K27, K56 and K122), three sites on H2A (K5, K137 and K142) and one site on H4 (K31), H2A1 (K73) and H2AX (K127) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…5 ). Sequence alignment analysis suggests that the Kla site on either H2A.zK137 or H2BK99 in T. gondii was also present in humans [ 3 ] and T. brucei [ 8 ]. Lactylation on H3K23, H3K27 and H4K31 in T. gondii is also conserved in human cells at the same site [ 3 ].…”

Section: Resultsmentioning

confidence: 99%

“…We found more lactylated proteins and sites in T. gondii than have been reported for the parasite Trypanosoma brucei , in which 387 Kla sites occurring on 257 lactylated proteins were identified [ 8 ]. The distinction in lactate dehydrogenase (LDH), which catalyzes the synthesis of lactate, possibly contributes to differences in Kla levels between the two parasites, given that the T. gondii genome encodes two LDH enzymes (TgLDH1 and TgLDH2) [ 32 , 33 ], while trypanosomes lack LDH [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…The lysine residue is one of the most frequently modified targets due to its function in the organization of protein spatial structure. Lysine lactylation (Kla) is a novel PTM that has been identified on both histone and nonhistone proteins in several organisms, including humans [ 3 , 4 ], mice [ 5 ], rice ( Oryza sativa ) [ 6 ], plant fungal pathogen ( Botrytis cinerea ) [ 7 ] and parasitic protozoan ( Trypanosoma brucei ) [ 8 ]. During this modification, the 72.021-Da of the l -lactate-derived lactyl group is covalently attached onto lysine residues via an enzymatic reaction mediated by the acetyl transferase p300 [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Systematic identification of the lysine lactylation in the protozoan parasite Toxoplasma gondii

Zhao

Liu

et al. 2022

Parasites Vectors

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Background Lysine lactylation (Kla) is a novelposttranslational modification (PTM) identified in histone and nonhistone proteins of several eukaryotic cells that directly activates gene expression and DNA replication. However, very little is known about the scope and cellular distribution of Kla in apicomplexan parasites despite its significance in public and animal health care. Methods Toxoplasma gondii, the causative agent of toxoplasmosis, is an obligate intracellular apicomplexan parasite that can infect different nucleated cell types of animals and humans. We used this parasite as a model organism and extracted the total protein of tachyzoites to produce the first global lysine lactylome profile of T. gondii through liquid chromatography–tandem mass spectrometry. We also investigated the level and localization of the Kla protein in T. gondii using western blotting and the indirect fluorescent antibody test (IFA), respectively. Results A total of 983 Kla sites occurring on 523 lactylated proteins were identified in the total protein extracted from Toxoplasma tachyzoites, the acute toxoplasmosis-causing stage. Bioinformatics analysis revealed that the lactylated proteins were evolutionarily conserved and involved in a wide variety of cellular functions, such as energy metabolism, gene regulation and protein biosynthesis. Subcellular localization analysis and IFA results further revealed that most of the lactylated T. gondii proteins were localized in the nucleus, indicating the potential impact of Kla on gene regulation in the T. gondii model. Notably, an extensive batch of parasite-specific proteins unique to phylum Apicomplexa is lactylated in T. gondii. Conclusions This study revealed that Kla is widespread in early dividing eukaryotic cells. Lactylated proteins, including a batch of unique parasite proteins, are involved in a remarkably diverse array of cellular functions. These valuable data will improve our understanding of the evolution of Kla and potentially provide the basis for developing novel therapeutic avenues. Graphical Abstract

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Global profiling of protein lactylation in Caenorhabditis elegans

Ding,

Yang,

Wang

et al. 2023

Proteomics

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Lactylation, as a novel posttranslational modification, is essential for studying the functions and regulation of proteins in physiological and pathological processes, as well as for gaining in‐depth knowledge on the occurrence and development of many diseases, including tumors. However, few studies have examined the protein lactylation of one whole organism. Thus, we studied the lactylation of global proteins in Caenorhabditis elegans to obtain an in vivo lactylome. Using an MS‐based platform, we identified 1836 Class I (localization probabilities > 0.75) lactylated sites in 487 proteins. Bioinformatics analysis showed that lactylated proteins were mainly located in the cytoplasm and involved in the tricarboxylic acid cycle (TCA cycle) and other metabolic pathways. Then, we evaluated the conservation of lactylation in different organisms. In total, 41 C. elegans proteins were lactylated and homologous to lactylated proteins in humans and rats. Moreover, lactylation on H4K80 was conserved in three species. An additional 238 lactylated proteins were identified in C. elegans for the first time. This study establishes the first lactylome database in C. elegans and provides a basis for studying the role of lactylation.

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Protein Lactylation Critically Regulates Energy Metabolism in the Protozoan Parasite Trypanosoma brucei

Cited by 30 publications

References 70 publications

Protein Lactylation and Metabolic Regulation of the Zoonotic Parasite Toxoplasma gondii

Protein Lactylation and Metabolic Regulation of the Zoonotic Parasite Toxoplasma gondii

Systematic identification of the lysine lactylation in the protozoan parasite Toxoplasma gondii

Global profiling of protein lactylation in Caenorhabditis elegans

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