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Proteomics profiling asthma induced-lysine acetylation.

ABSTRACT: Asthma is a chronic inflammatory disease that has been extensively studied for many years. However, finding a complete cure remains a significant challenge. Protein acetylation, especially histone acetylation, plays a significant role in the anti-asthma process. Histone deacetylation inhibitors (HDACi) have been shown to have a curative effect on asthma in clinical practice. An asthmatic mouse model was created by ovalbumin induction. Proteome and acetylproteome analysis were performed on lung tissues. HDACi were tested in the asthmatic mice. A total of 5346 proteins and 581 acetylation sites were identified, among which 154 proteins and 68 acetylation peptides were significantly altered by asthma. Many activated and deactivated processes, pathways, and protein groups were identified through bioinformatics analysis. Sequence motif preference analysis gave rise to a novel Kac-related core histone region, -KAXXK-, which was postulated as a key regulatory unit of histone acetylation. Asthma involves a variety of proteome dynamics and is controlled by protein lysine acetylation through the core motif -KAXXK-. These findings provide novel avenues to target and treat asthma.

SUBMITTER: Su XM

PROVIDER: S-EPMC7332788 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Proteomics profiling asthma induced-lysine acetylation.

Su Xin-Ming XM Ren Yuan Y Li Meng-Lu ML Bai Shi-Yao SY Yu Na N Kong Ling-Fei LF Kang Jian J

EXCLI journal 20200604

Asthma is a chronic inflammatory disease that has been extensively studied for many years. However, finding a complete cure remains a significant challenge. Protein acetylation, especially histone acetylation, plays a significant role in the anti-asthma process. Histone deacetylation inhibitors (HDACi) have been shown to have a curative effect on asthma in clinical practice. An asthmatic mouse model was created by ovalbumin induction. Proteome and acetylproteome analysis were performed on lung t ...[more]

PMID: 32636726

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Project description:Lysine acetylation is a highly conserved posttranslational modification that plays essential roles in multiple biological functions in a variety of organisms. Deinococcus radiodurans (D. radiodurans) is famous for its extreme resistance to radiation. However, few studies have focused on the lysine acetylation in D. radiodurans. In the present study, antibody enrichment technology and high-resolution liquid chromatography mass spectrometry are used to perform a global analysis of lysine acetylation of D. radiodurans. We create the largest acetylome data set in D. radiodurans to date, totally identifying 4,364 lysine acetylation sites on 1,410 acetylated proteins. Strikingly, of the 3,085 proteins annotated by the uniport database, 45.7% of proteins are acetylated in D. radiodurans. In particular, the glutamate (G) preferentially appears at the -1 and +1 positions of acetylated lysine residues by motif analysis. The acetylated proteins are involved in metabolic pathways, propanoate metabolism, carbon metabolism, fatty acid metabolism, and the tricarboxylic acid cycle. Protein-protein interaction networks demonstrate that four clusters are involved in DNA damage repair, including homologous recombination, mismatch repair, nucleotide excision repair, and base excision repair, which suggests that acetylation plays an indispensable role in the extraordinary capacity to survive high levels of ionizing radiation. Taken together, we report the most comprehensive lysine acetylation in D. radiodurans for the first time, which is of great significance to reveal its robust resistance to radiation. IMPORTANCE D. radiodurans is distinguished by the most radioresistant organism identified to date. Lysine acetylation is a highly conserved posttranslational modification that plays an essential role in the regulation of many cellular processes and may contribute to its extraordinary radioresistance. We integrate acetyl-lysine enrichment strategy, high-resolution mass spectrometry, and bioinformatics to profile the lysine acetylated proteins for the first time. It is striking that almost half of the total annotated proteins are identified as acetylated forms, which is the largest acetylome data set reported in D. radiodurans to date. The acetylated proteins are involved in metabolic pathways, propanoate metabolism, carbon metabolism, fatty acid metabolism, and the tricarboxylic acid cycle. The results of this study reinforce the notion that acetylation plays critical regulatory roles in diverse aspects of the cellular process, especially in DNA damage repair and metabolism. It provides insight into the roles of lysine acetylation in the robust resistance to radiation.

Project description:Epigenetic processes that regulate histone acetylation play an essential role in behavioral and molecular responses to cocaine. To date, however, only a small fraction of the mechanisms involved in the addiction-associated acetylome have been investigated. Members of the bromodomain and extraterminal (BET) family of epigenetic "reader" proteins (BRD2, BRD3, BRD4, and BRDT) bind acetylated histones and serve as a scaffold for the recruitment of macromolecular complexes to modify chromatin accessibility and transcriptional activity. The role of BET proteins in cocaine-induced plasticity, however, remains elusive. Here, we used behavioral, pharmacological, and molecular techniques to examine the involvement of BET bromodomains in cocaine reward. Of the BET proteins, BRD4, but not BRD2 or BRD3, was significantly elevated in the nucleus accumbens (NAc) of mice and rats following repeated cocaine injections and self-administration. Systemic and intra-accumbal inhibition of BRD4 with the BET inhibitor, JQ1, attenuated the rewarding effects of cocaine in a conditioned place preference procedure but did not affect conditioned place aversion, nor did JQ1 alone induce conditioned aversion or preference. Investigating the underlying mechanisms, we found that repeated cocaine injections enhanced the binding of BRD4, but not BRD3, to the promoter region of Bdnf in the NAc, whereas systemic injection of JQ1 attenuated cocaine-induced expression of Bdnf in the NAc. JQ1 and siRNA-mediated knockdown of BRD4 in vitro also reduced expression of Bdnf. These findings indicate that disrupting the interaction between BET proteins and their acetylated lysine substrates may provide a new therapeutic avenue for the treatment of drug addiction.Significance statementProteins involved in the "readout" of lysine acetylation marks, referred to as BET bromodomain proteins (including BRD2, BRD3, BRD4, and BRDT), have been shown to be key regulators of chromatin dynamics and disease, and BET inhibitors are currently being studied in several clinical trials. However, their role in addiction-related phenomena remains unknown. In the current studies, we revealed that BRD4 is elevated in the nucleus accumbens and recruited to promoter regions of addiction-related genes following repeated cocaine administration, and that inhibition of BRD4 attenuates transcriptional and behavioral responses to cocaine. Together, these studies reveal that BET inhibitors may have therapeutic utility in the treatment of cocaine addiction.

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Proteomics profiling asthma induced-lysine acetylation.

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Proteomics profiling asthma induced-lysine acetylation.

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