Proteomic characterization of post-translational modifications in drug discovery

Zhai, Linhui; Chen, Kai-feng; Hao, Bingbing; Tan, Minjia

doi:10.1038/s41401-022-01017-y

Cited by 20 publications

(8 citation statements)

References 203 publications

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“…However, the limitations associated with off- target effects, as well as the presence of heterogeneous and heterozygote knockouts, undermine the dependability of its findings(Chan et al, 2022). PTM omics, on the other hand, presents a potent methodology for comprehensively characterizing PTMs at a system-wide level and has found extensive application in the identification of potential drug targets and the elucidation of drug mechanisms(Zhai et al, 2022). Nevertheless, it is important to note that while PTM omics can identify proteins implicated in drug action, it does not ascertain whether these proteins exert a positive or negative influence on the efficacy of the drug.…”

Section: Discussionmentioning

confidence: 99%

CCT3 drives Sorafenib resistance by inhibiting TFRC-mediated iron uptake in HCC

Zhu,

Liu,

Meng

et al. 2023

Preprint

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Sorafenib is commonly utilized in the management of advanced hepatocellular carcinoma (HCC). However, its efficacy in extending patients’ survival is hindered by the development of drug resistance. By employing protein posttranslational modification (PTM) omics, including acetylome, phosphoproteome, and ubiquitinome, in conjunction with genome-wide CRISPR/Cas9 knockout library screening, we have successfully identified chaperonin containing TCP1 subunit 3 (CCT3) as a key factor contributing to Sorafenib resistance. Furthermore, we observed a reduction in the ubiquitination of CCT3 at lysine 21 (K21) subsequent to Sorafenib treatment. This study provides evidence that CCT3 hinders the recycling of transferrin receptor protein 1 (TFRC) by interacting with alpha-actinin-4 (ACTN4), which is influenced by K6-linked ubiquitination on K21. Depleting CCT3 increased the susceptibility of cells to Sorafenib-induced ferroptosis, while reintroducing CCT3 through transfection restored resistance to ferroptosis. Additionally, impairing ACTN4 or TFRC depletion compromised CCT3’s ability to inhibit Sorafenib-induced ferroptosis. In summary, targeting CCT3 presents a potential strategy for overcoming Sorafenib resistance in HCC.

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Section: Discussionmentioning

confidence: 99%

CCT3 drives Sorafenib resistance by inhibiting TFRC-mediated iron uptake in HCC

Zhu,

Liu,

Meng

et al. 2023

Preprint

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“…Enzyme-catalyzed covalent modifications of amino acids such as phosphorylation, ubiquitination, glycosylation, and ADP-ribosylation are post-translational modifications (PTMs). PTMs regulate various processes related to cellular homeostasis [ 125 ]. The biological complexity and the potentially ephemeral nature of PTMs make them challenging to decipher; but innovative mass spectrometry technologies have enabled their widespread investigations.…”

Section: Mass Spectrometry and Adp-ribosylationmentioning

confidence: 99%

PARPs and ADP-Ribosylation in Chronic Inflammation: A Focus on Macrophages

et al. 2023

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Aberrant adenosine diphosphate-ribose (ADP)-ribosylation of proteins and nucleic acids is associated with multiple disease processes such as infections and chronic inflammatory diseases. The poly(ADP-ribose) polymerase (PARP)/ADP-ribosyltransferase (ART) family members promote mono- or poly-ADP-ribosylation. Although evidence has linked PARPs/ARTs and macrophages in the context of chronic inflammation, the underlying mechanisms remain incompletely understood. This review provides an overview of literature focusing on the roles of PARP1/ARTD1, PARP7/ARTD14, PARP9/ARTD9, and PARP14/ARTD8 in macrophages. PARPs/ARTs regulate changes in macrophages during chronic inflammatory processes not only via catalytic modifications but also via non-catalytic mechanisms. Untangling complex mechanisms, by which PARPs/ARTs modulate macrophage phenotype, and providing molecular bases for the development of new therapeutics require the development and implementation of innovative technologies.

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“…Many angles of personalized medicine, such as diagnostic improvements, systems biology [1], drug screening/mechanisms of action [2,3] and bioinformatics, require the deployment of quantitatively precise human proteomics datasets to make omics analysis actionable at a clinical level [4][5][6]. Biomedical proteomics implements protein research to elucidate disease-affected proteotypes and to determine protein features such as origin, localization [7,8], interactions [9][10][11], posttranslational modifications [12][13][14][15] and protein imbalance [16,17] in human malignancies. Multiple contributions were submitted to this Special Issue, with four original articles and two reviews being accepted for publication.…”

mentioning

confidence: 99%