PXD054686

PXD054686 is an original dataset announced via ProteomeXchange.

Title	Acetylation of Proximal Cysteine-Lysine Pairs by Alcohol Metabolism
Description	Alcohol consumption induces hepatocyte damage through complex processes involving oxidative stress and disrupted metabolism. Combined, these factors alter proteomic and epigenetic marks providing a critical opportunity to identify therapeutic targets. Indeed, alcohol-induced protein acetylation is a key post-translational modification (PTM) that regulates hepatic metabolism and is associated with the pathogenesis of alcohol-associated liver disease (ALD). Interestingly, recent evidence suggests lysine acetylation occurs when a proximal cysteine residue is within ~15 Å of a lysine residue, referred to as a cysteine-lysine (Cys-Lys) pair. Here, acetylation can occur through the transfer of an acetyl moiety via an S à N acetyl transfer reaction. Alcohol-mediated hepatic redox stress is known to occur coincident with lysine acetylation, but the biochemical mechanisms related to cysteine and lysine crosstalk within ALD remain unexplored. A chronic murine model of ALD was employed to quantify hepatic cysteine redox and lysine acetylation, revealing that alcohol metabolism significantly reduced the cysteine proteome and increased protein acetylation. Interrogating both cysteine redox and lysine acetylation datasets, 1,281 proteins were mapped by AlphaFold2 to quantify distances between 557,815 cysteine and lysine residues. This process identified 388,698 Cys-Lys pairs that were further used to evaluate thiol redox signaling. Our analysis reveals that alcohol metabolism induces redox changes and acetylation selectively on proximal Cys-Lys pairs with an odds ratio of 1.89 (p< 0.0001). We also identified key redox signaling hubs embedded in metabolic pathways associated with ALD, including lipid metabolism, the TCA cycle, and the electron transport chain. Specific protein targets embedded across these pathways include Echs1, Glrx5, Decr2, and Adh1, among many others. Interestingly, these proximal Cys-Lys exist as four major protein motifs represented by the number of Cys and Lys residues that are pairing (Cysx-Lysx). These motifs include Cys1:Lys1, Cysx:Lys1, Cys1:Lysx and Cysx:Lysx each with a unique microenvironment likely indicative of the mode of enzymatic regulation occurring. The motifs are composed of functionally relevant amino acids altered within ALD, identifying sites of therapeutic potential. Furthermore, these unique Cys-Lys redox signatures are translationally relevant as revealed by orthologous comparison with severe alcohol-associated hepatitis (SAH) explants, revealing numerous pathogenic thiol redox signals in these patients.
HostingRepository	PRIDE
AnnounceDate	2024-12-17
AnnouncementXML	Submission_2024-12-17_14:31:50.861.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD054686
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Cole Michel
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; deamidated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-07 17:52:25	ID requested
⏵ 1	2024-12-17 14:31:51	announced

10.6019/PXD054686;

10.1016/J.REDOX.2024.103462;

submitter keyword: Alcohol-Associated Liver Disease, Protein Modeling, Mass Spectrometry,Cysteine Proteomics, Redox, Acetylation

Kristofer Fritz
contact affiliation	University of Colorado Skaggs School of Pharmacy
contact email	kristofer.fritz@cuanschutz.edu
lab head
Cole Michel
contact affiliation	Univeristy of Colorado - Skaggs School of Pharmacy
contact email	cole.michel@cuanschutz.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054686
     1. Label: PRIDE project
     2. Name: Acetylation of Proximal Cysteine-Lysine Pairs by Alcohol Metabolism