Dataset Information

Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway.

ABSTRACT: Short-chain fatty acids and their corresponding acyl-CoAs sit at the crossroads of metabolic pathways and play important roles in diverse cellular processes. They are also precursors for protein post-translational lysine acylation modifications. A noteworthy example is the newly identified lysine 2-hydroxyisobutyrylation (Khib) that is derived from 2-hydroxyisobutyrate and 2-hydroxyisobutyryl-CoA. Histone Khib has been shown to be associated with active gene expression in spermatogenic cells. However, the key elements that regulate this post-translational lysine acylation pathway remain unknown. This has hindered characterization of the mechanisms by which this modification exerts its biological functions. Here we show that Esa1p in budding yeast and its homologue Tip60 in human could add Khib to substrate proteins both in vitro and in vivo. In addition, we have identified HDAC2 and HDAC3 as the major enzymes to remove Khib. Moreover, we report the first global profiling of Khib proteome in mammalian cells, identifying 6 548 Khib sites on 1 725 substrate proteins. Our study has thus discovered both the "writers" and "erasers" for histone Khib marks, and major Khib protein substrates. These results not only illustrate the landscape of this new lysine acylation pathway, but also open new avenues for studying diverse functions of cellular metabolites associated with this pathway.

SUBMITTER: Huang H

PROVIDER: S-EPMC5752845 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway.

Huang He H Luo Zhouqing Z Qi Shankang S Huang Jing J Xu Peng P Wang Xiuxuan X Gao Li L Li Fangyi F Wang Jian J Zhao Wenhui W Gu Wei W Chen Zhucheng Z Dai Lunzhi L Dai Junbiao J Zhao Yingming Y

Cell research 20171201 1

Short-chain fatty acids and their corresponding acyl-CoAs sit at the crossroads of metabolic pathways and play important roles in diverse cellular processes. They are also precursors for protein post-translational lysine acylation modifications. A noteworthy example is the newly identified lysine 2-hydroxyisobutyrylation (K<sub>hib</sub>) that is derived from 2-hydroxyisobutyrate and 2-hydroxyisobutyryl-CoA. Histone K<sub>hib</sub> has been shown to be associated with active gene expression in s ...[more]

PMID: 29192674

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Project description:Candida albicans is the most common human fungal pathogen, causing diseases ranging from mucosal to systemic infections for both immunocompetent and immunocompromised individuals. Lysine 2-hydroxyisobutyrylation is a highly conserved posttranslational modification found in a wide variety of organisms. In this study, we surveyed the biological impact of 2-hydroxyisobutyrylation on lysine residuals (Khib) in C. albicans Using an antibody enrichment approach along with the traditional liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, we analyzed the pattern of Khib-modified proteins and sites in one wild-type strain of C. albicans We identified 1,438 Khib-modified proteins with 6,659 modified sites in this strain, and a more detailed bioinformatics analysis indicated that the Khib-modified proteins are involved in a wide range of cellular functions with diverse subcellular locations. Functional enrichment analysis featured several prominent functional pathways, including ribosome, biosynthesis of antibiotics, biosynthesis of secondary metabolites, biosynthesis of amino acids and carbon metabolism, of which the ribosome pathway is the most affected pathway. Even compared with the reported numbers of lysine acetylation (Kac) and succinylation (Ksuc) sites, the numbers of Khib-modified sites on ribosomal proteins remained the highest for C. albicans These bioinformatic results suggest that 2-hydroxyisobutyrylation may play an indispensable role in the regulation of the ribosomal biogenesis and protein translation. Findings in this study may provide new insights for studying posttranslational modification (PTM)-associated mechanisms in fungal development and pathogenicity.IMPORTANCEC. albicans is one of the most commonly reported fungal pathogens in mucosal and systemic infections. A better understanding of its growth habits and metabolic processes in the host should help improve defense strategies. The newly discovered protein posttranslational modification (PTM) on histones is one epigenetic mechanism which has been linked to many pathogenic events, including cancers. The types of PTM and their pathogenic roles in C. albicans are still somewhat poorly understood, even though studies of C. albicans based on acetylation inhibitors have shed some light on their function, and it seems that PTMs regulate pathogenic adhesion factors. Here, we quantified and analyzed the occurrence of lysine 2-hydroxyisobutyrylation (Khib) in C. albicans The Khib-modified proteins are enriched with respect to carbon metabolism, ribosomal biogenesis, and protein translation in C. albicans.

Project description:BackgroundLysine 2-hydroxyisobutyrylation (Khib) is a novel and conserved post-translational modification (PTM). Frankliniella occidentalis are economically important agricultural pests globally and also notorious for vectoring destructive plant viruses. To better study the disease transmission mechanism of F. occidentalis, it is necessary to conduct in-depth analysis of it. So far, no Khib modification of insects has been reported.ResultsIn this study, a proteome-wide analysis of Khib modifications in F. occidentalis was analyzed for the first time through the combination of high performance liquid chromatography fractionation technology and 2-hydroxyisobutyrylated peptide enrichment and other advanced technologies, 4093 Khib sites were identified on 1125 modified proteins. Bioinformatics and functional enrichment analyses showed that Khib-modified proteins were significantly enriched in many cell compartments and pathways, especially related to various cellular components and biological processes, and were more concentrated in ribosomes and proteasome subunits, involved in energy metabolism, protein synthesis and degradation, compared to the other nine species including Japonica rice, Homo sapiens, P. patens, Botrytis, Ustilaginoidea virens, Saccharomyces cerevisiae, T. gondii, C. albicans, and F. oxysporum. And Khib sites on virus-interacting insect proteins were discovered for the first time, such as cyclophilin and endoCP-GN.ConclusionsAfter three repeated experiments, we found a total of 4093 Khib sites on 1125 proteins. These modified proteins are mainly concentrated in ribosomes and proteasome subunits, and are widely involved in a variety of critical biological activities and metabolic processes of F. occidentalis. In addition, for the first time, Khib modification sites are found on the proteome of F. occidentalis, and these sites could be acted as for the virus interaction, including cyclophilin and endoCP-GN. The global map of 2-hydroxyisobutyrylation in thrips is an invaluable resource to better understand the biological processes of thrips and provide new means for disease control and mitigation of pest damage to crops.

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Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway.

Publications

Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway.

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