SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells

Tong, Yuru; Guo, Dong; Lin, Shuhai; Liang, Jiazhen; Yang, Dianqiang; Ma, Chunmin; Shao, Fei; Li, Min; Yu, Qiujing; Jiang, Yuhui; Li, Lei; Fang, Jing; Yu, Rilei; Lu, Zhimin

doi:10.1016/j.molcel.2021.04.002

Cited by 109 publications

(90 citation statements)

References 41 publications

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“…Our second best scoring substrate, K311 of Glutaminase ( reweighted score : − 1134, GLS), plays an important part in regulating GLS oligomerization which is crucial for the activation of the enzyme 74 . Removal of the acetyl group induces oligomerization and activation of GLS which reduces oxidative stress in cancer cells therefore promoting their survival 75 . Glycolytic enzymes have been proposed to be substrates of HDAC6 76 , and our acetylome screen identified two glycolytic enzymes shown to interact with HDAC6, phosphoglycerate kinase 1 (PGK1) 77 and pyruvate kinase muscle (PKM) 78 .…”

Section: Discussionmentioning

confidence: 99%

Structure-based prediction of HDAC6 substrates validated by enzymatic assay reveals determinants of promiscuity and detects new potential substrates

Varga

Diffley

Leng

et al. 2022

Sci Rep

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Histone deacetylases play important biological roles well beyond the deacetylation of histone tails. In particular, HDAC6 is involved in multiple cellular processes such as apoptosis, cytoskeleton reorganization, and protein folding, affecting substrates such as ɑ-tubulin, Hsp90 and cortactin proteins. We have applied a biochemical enzymatic assay to measure the activity of HDAC6 on a set of candidate unlabeled peptides. These served for the calibration of a structure-based substrate prediction protocol, Rosetta FlexPepBind, previously used for the successful substrate prediction of HDAC8 and other enzymes. A proteome-wide screen of reported acetylation sites using our calibrated protocol together with the enzymatic assay provide new peptide substrates and avenues to novel potential functional regulatory roles of this promiscuous, multi-faceted enzyme. In particular, we propose novel regulatory roles of HDAC6 in tumorigenesis and cancer cell survival via the regulation of EGFR/Akt pathway activation. The calibration process and comparison of the results between HDAC6 and HDAC8 highlight structural differences that explain the established promiscuity of HDAC6.

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Section: Discussionmentioning

confidence: 99%

Structure-based prediction of HDAC6 substrates validated by enzymatic assay reveals determinants of promiscuity and detects new potential substrates

Varga

Diffley

Leng

et al. 2022

Sci Rep

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“…Changes in lysine acetylation in key enzymes may impair their activities and alter the metabolic homeostasis of the follicular microenvironment of oocyte maturation and embryonic development ( 36 ). Enhancement of glutaminase (GLS) K311 succinylation may promote tumor cell survival and tumor growth by increasing glutaminolysis and the production of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione through counteracting the oxidative stress ( 37 ). The crosstalk between acetylation and ubiquitination in AMPA receptors (AMPARs) presents crucial roles in synaptic plasticity and memory ( 38 ).…”

Section: Introductionmentioning

confidence: 99%

dbPTM in 2022: an updated database for exploring regulatory networks and functional associations of protein post-translational modifications

Luo

et al. 2021

Nucleic Acids Research

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Protein post-translational modifications (PTMs) play an important role in different cellular processes. In view of the importance of PTMs in cellular functions and the massive data accumulated by the rapid development of mass spectrometry (MS)-based proteomics, this paper presents an update of dbPTM with over 2 777 000 PTM substrate sites obtained from existing databases and manual curation of literature, of which more than 2 235 000 entries are experimentally verified. This update has manually curated over 42 new modification types that were not included in the previous version. Due to the increasing number of studies on the mechanism of PTMs in the past few years, a great deal of upstream regulatory proteins of PTM substrate sites have been revealed. The updated dbPTM thus collates regulatory information from databases and literature, and merges them into a protein-protein interaction network. To enhance the understanding of the association between PTMs and molecular functions/cellular processes, the functional annotations of PTMs are curated and integrated into the database. In addition, the existing PTM-related resources, including annotation databases and prediction tools are also renewed. Overall, in this update, we would like to provide users with the most abundant data and comprehensive annotations on PTMs of proteins. The updated dbPTM is now freely accessible at https://awi.cuhk.edu.cn/dbPTM/.

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“… 227 The two glutaminase isoforms are liver-type (GLS2) and kidney-type (GLS), in which the site 311 of GLS is activated by succinylation to resist oxidative stress and promote tumor survival by increasing glutamine decomposition and NADPH/glutathione production. 228 The growth of renal clear cell carcinoma can be regulated by the interaction between succinate dehydrogenase complex subunit A (SDHA) and SIRT5 and the level of succinylation. 229 Many small G-proteins, including Ras, Rho, and Rac families, are prenylated with farnesyl or geranylgeranyl groups to help their membrane location.…”

Section: The Biological Effect Of Ptms On Tumor Cells In Tmementioning

confidence: 99%

Insights into the post-translational modification and its emerging role in shaping the tumor microenvironment

Wen

Zhang

et al. 2021

Sig Transduct Target Ther

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More and more in-depth studies have revealed that the occurrence and development of tumors depend on gene mutation and tumor heterogeneity. The most important manifestation of tumor heterogeneity is the dynamic change of tumor microenvironment (TME) heterogeneity. This depends not only on the tumor cells themselves in the microenvironment where the infiltrating immune cells and matrix together forming an antitumor and/or pro-tumor network. TME has resulted in novel therapeutic interventions as a place beyond tumor beds. The malignant cancer cells, tumor infiltrate immune cells, angiogenic vascular cells, lymphatic endothelial cells, cancer-associated fibroblastic cells, and the released factors including intracellular metabolites, hormonal signals and inflammatory mediators all contribute actively to cancer progression. Protein post-translational modification (PTM) is often regarded as a degradative mechanism in protein destruction or turnover to maintain physiological homeostasis. Advances in quantitative transcriptomics, proteomics, and nuclease-based gene editing are now paving the global ways for exploring PTMs. In this review, we focus on recent developments in the PTM area and speculate on their importance as a critical functional readout for the regulation of TME. A wealth of information has been emerging to prove useful in the search for conventional therapies and the development of global therapeutic strategies.

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SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells

Cited by 109 publications

References 41 publications

Structure-based prediction of HDAC6 substrates validated by enzymatic assay reveals determinants of promiscuity and detects new potential substrates

Structure-based prediction of HDAC6 substrates validated by enzymatic assay reveals determinants of promiscuity and detects new potential substrates

dbPTM in 2022: an updated database for exploring regulatory networks and functional associations of protein post-translational modifications

Insights into the post-translational modification and its emerging role in shaping the tumor microenvironment

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