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N-terminal cysteine acetylation and oxidation patterns may define protein stability.

ABSTRACT: Oxygen homeostasis is maintained in plants and animals by O₂-sensing enzymes initiating adaptive responses to low O₂ (hypoxia). Recently, the O₂-sensitive enzyme ADO was shown to initiate degradation of target proteins RGS4/5 and IL32 via the Cysteine/Arginine N-degron pathway. ADO functions by catalysing oxidation of N-terminal cysteine residues, but despite multiple proteins in the human proteome having an N-terminal cysteine, other endogenous ADO substrates have not yet been identified. This could be because alternative modifications of N-terminal cysteine residues, including acetylation, prevent ADO-catalysed oxidation. Here we investigate the relationship between ADO-catalysed oxidation and NatA-catalysed acetylation of a broad range of protein sequences with N-terminal cysteines. We present evidence that human NatA catalyses N-terminal cysteine acetylation in vitro and in vivo. We then show that sequences downstream of the N-terminal cysteine dictate whether this residue is oxidised or acetylated, with ADO preferring basic and aromatic amino acids and NatA preferring acidic or polar residues. In vitro, the two modifications appear to be mutually exclusive, suggesting that distinct pools of N-terminal cysteine proteins may be acetylated or oxidised. These results reveal the sequence determinants that contribute to N-terminal cysteine protein modifications, with implications for O₂-dependent protein stability and the hypoxic response.

SUBMITTER: Heathcote KC

PROVIDER: S-EPMC11199558 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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N-terminal cysteine acetylation and oxidation patterns may define protein stability.

Heathcote Karen C KC Keeley Thomas P TP Myllykoski Matti M Lundekvam Malin M McTiernan Nina N Akter Salma S Masson Norma N Ratcliffe Peter J PJ Arnesen Thomas T Flashman Emily E

Nature communications 20240625 1

Oxygen homeostasis is maintained in plants and animals by O2-sensing enzymes initiating adaptive responses to low O2 (hypoxia). Recently, the O2-sensitive enzyme ADO was shown to initiate degradation of target proteins RGS4/5 and IL32 via the Cysteine/Arginine N-degron pathway. ADO functions by catalysing oxidation of N-terminal cysteine residues, but despite multiple proteins in the human proteome having an N-terminal cysteine, other endogenous ADO substrates ha ...[more]

PMID: 38918375

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Project description:BackgroundHistone acetylation modification is one of the most common epigenetic methods used to regulate chromatin structure, DNA repair, and gene expression. Existing research has focused on the importance of histone acetylation in regulating tumorigenicity, tumor progression, and tumor microenvironment (TME) but has not explored the potential roles and interactions of histone acetylation regulators in TME cell infiltration, drug sensitivity, and immunotherapy.MethodsThe mRNA expression and genetic alterations of 36 histone acetylation regulators were analyzed in 1599 hepatocellular carcinoma (HCC) samples. The unsupervised clustering method was used to identify the histone acetylation patterns. Then, based on their differentially expressed genes (DEGs), an HAscore model was constructed to quantify the histone acetylation patterns and related subtypes of individual samples. Lastly, the relationship between HAscore and transcription background, tumor clinical features, characteristics of TME, drug response, and efficacy of immunotherapy were analyzed.ResultsWe identified three histone acetylation patterns characterized by high, medium, and low HAscore. Patients with HCC in the high HAscore group experienced worse overall survival time, and the cancer-related malignant pathways were more active in the high HAscore group, comparing to the low HAscore group. The high HAscore group was characterized by an immunosuppressive subtype because of the high infiltration of immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells. Following validation, the HAscore was highly correlated with the sensitivity of anti-tumor drugs; 116 therapeutic agents were found to be associated with it. The HAscore was also correlated with the therapeutic efficacy of the PD-L1 and PD-1 blockade, and the response ratio was significantly higher in the low HAscore group.ConclusionTo the best of our knowledge, our study is the first to provide a comprehensive analysis of 36 histone acetylation regulators in HCC. We found close correlations between histone acetylation patterns and tumor malignant pathways and TME. We also analyzed the therapeutic value of the HAscore in targeted therapy and immunotherapy. This work highlights the interactions and potential clinical utility of histone acetylation regulators in treatment of HCC and improving patient outcomes.

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N-terminal cysteine acetylation and oxidation patterns may define protein stability.

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N-terminal cysteine acetylation and oxidation patterns may define protein stability.

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