N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA914318 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22830900.fastq.gz | Fastqsanger.gz | |||
| SRR22830901.fastq.gz | Fastqsanger.gz | |||
| SRR22830902.fastq.gz | Fastqsanger.gz | |||
| SRR22830903.fastq.gz | Fastqsanger.gz | |||
| SRR22830904.fastq.gz | Fastqsanger.gz |
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Project description:Most eukaryotic proteins are N-terminally acetylated, but the functional impact on a global scale has remained obscure. Using genome-wide CRISPR knockout screens in human cells, we reveal a strong genetic dependency between a major N-terminal acetyltransferase and specific ubiquitin ligases. Biochemical analyses uncover that both the ubiquitin ligase complex UBR4-KCMF1 and the acetyltransferase NatC recognize proteins bearing an unacetylated N-terminal methionine followed by a hydrophobic residue. NatC KO-induced protein degradation and phenotypes are reversed by UBR knockdown, demonstrating the central cellular role of this interplay. We reveal that loss of Drosophila NatC is associated with male sterility, reduced longevity, and age-dependent loss of motility due to developmental muscle defects. Remarkably, muscle-specific overexpression of UbcE2M, one of the proteins targeted for NatC KO mediated degradation, suppresses defects of NatC deletion. In conclusion, NatC-mediated N-terminal acetylation acts as a protective mechanism against protein degradation, which is relevant for increased longevity and motility.
2023-09-18 | GSE221447 | GEO
Project description:Most eukaryotic proteins are N-terminally acetylated, but the functional impact on a global scale has remained obscure. Using genome-wide CRISPR knockout screens in human cells, we reveal a strong genetic dependency between a major N-terminal acetyltransferase and specific ubiquitin ligases. Biochemical analyses uncover that both the ubiquitin ligase complex UBR4-KCMF1 and the acetyltransferase NatC recognize proteins bearing an unacetylated N-terminal methionine followed by a hydrophobic residue. NatC KO-induced protein degradation and phenotypes are reversed by UBR knockdown, demonstrating the central cellular role of this interplay. We reveal that loss of Drosophila NatC is associated with male sterility, reduced longevity, and age-dependent loss of motility due to developmental muscle defects. Remarkably, muscle-specific overexpression of UbcE2M, one of the proteins targeted for NatC KO-mediated degradation, suppresses defects of NatC deletion. In conclusion, NatC-mediated N-terminal acetylation acts as a protective mechanism against protein degradation, which is relevant for increased longevity and motility.
| S-EPMC10611716 | biostudies-literature
Project description:H3K4 methylation is a conserved histone modification crucial for gene regulation, yet the post-translational modifications of the Set1-COMPASS complex remain largely unexplored. This study elucidates the significance of N-terminal acetylation in modulating H3K4 methylation patterns. Firstly, loss of NatA complex resulted in a significant decrease in H3K4me3 levels and a shift of H3K4me2 from 5' transcribed regions to promoters. Importantly, NatA physically interacted with the Set1-COMPASS complex and facilitated N-terminal acetylation of the Shg1 subunit. Surprisingly, deletion of SHG1 or mutation of the acetylation site (A2P) in Shg1 led to reduced H3K4 methylation in cells lacking Spp1. Additionally, NatB complex also contributed to H3K4 methylation regulation, potentially through N-terminal acetylation of Swd1. These findings highlight the novel role of N-terminal acetylation in fine-tuning the function of the Set1-COMPASS complex and shaping H3K4 methylation patterns. This study sheds light on the intricate regulation of H3K4 methylation and emphasizes the significance of N-terminal acetylation as a regulatory mechanism in this process.
2024-05-31 | GSE238069 | GEO
Project description:H3K4 methylation is a conserved histone modification crucial for gene regulation, yet the post-translational modifications of the Set1-COMPASS complex remain largely unexplored. This study elucidates the significance of N-terminal acetylation in modulating H3K4 methylation patterns. Firstly, loss of NatA complex resulted in a significant decrease in H3K4me3 levels and a shift of H3K4me2 from 5' transcribed regions to promoters. Importantly, NatA physically interacted with the Set1-COMPASS complex and facilitated N-terminal acetylation of the Shg1 subunit. Surprisingly, deletion of SHG1 or mutation of the acetylation site (A2P) in Shg1 led to reduced H3K4 methylation in cells lacking Spp1. Additionally, NatB complex also contributed to H3K4 methylation regulation, potentially through N-terminal acetylation of Swd1. These findings highlight the novel role of N-terminal acetylation in fine-tuning the function of the Set1-COMPASS complex and shaping H3K4 methylation patterns. This study sheds light on the intricate regulation of H3K4 methylation and emphasizes the significance of N-terminal acetylation as a regulatory mechanism in this process.
2024-05-31 | GSE237939 | GEO
Project description:H3K4 methylation is a conserved histone modification crucial for gene regulation, yet the post-translational modifications of the Set1-COMPASS complex remain largely unexplored. This study elucidates the significance of N-terminal acetylation in modulating H3K4 methylation patterns. Firstly, loss of NatA complex resulted in a significant decrease in H3K4me3 levels and a shift of H3K4me2 from 5' transcribed regions to promoters. Importantly, NatA physically interacted with the Set1-COMPASS complex and facilitated N-terminal acetylation of the Shg1 subunit. Surprisingly, deletion of SHG1 or mutation of the acetylation site (A2P) in Shg1 led to reduced H3K4 methylation in cells lacking Spp1. Additionally, NatB complex also contributed to H3K4 methylation regulation, potentially through N-terminal acetylation of Swd1. These findings highlight the novel role of N-terminal acetylation in fine-tuning the function of the Set1-COMPASS complex and shaping H3K4 methylation patterns. This study sheds light on the intricate regulation of H3K4 methylation and emphasizes the significance of N-terminal acetylation as a regulatory mechanism in this process.
2024-05-31 | GSE253436 | GEO
Project description:Loss of function during ageing is accompanied by transcriptional drift, altering gene expression and contributing to a variety of age-related diseases. CREB-regulated transcriptional coactivators (CRTCs) have emerged as key regulators of gene expression that might be targeted to promote longevity. Here, we define the role of the Caenorhabditis elegans CRTC-1 in the epigenetic regulation of longevity. Endogenous CRTC-1 binds chromatin factors, including components of the COMPASS complex, which trimethylates lysine 4 on histone H3 (H3K4me3). CRISPR editing of endogenous CRTC-1 reveals that the CREB-binding domain in neurons is specifically required for H3K4me3-dependent longevity. However, this effect is independent of CREB but instead acts via the transcription factor AP-1. Strikingly, CRTC-1 also mediates global histone acetylation levels, and this acetylation is essential for H3K4me3-dependent longevity. Indeed, overexpression of an acetyltransferase enzyme is sufficient to promote longevity in wild-type worms. CRTCs, therefore, link energetics to longevity by critically fine-tuning histone acetylation and methylation to promote healthy ageing.
2023-08-02 | GSE239572 | GEO
Project description:N-terminal acetylation (NTA) is one of the most abundant protein modifications in eukaryotes and is catalysed in humans by seven N-acetyltransferases. In this study, we investigated the Arabidopsis thaliana NatB catalytic (NAA20) and auxiliary subunit (NAA25) and their influence on protein N-terminal acetylation using the SILProNAQ approach
2019-11-21 | PXD016209 | Pride
Project description:N-terminal (Nt) acetylation, catalyzed by N-terminal acetyltransferases (NATs), has emerged as an important co-translational modification in eukaryotes, and involves the transfer of the acetyl moiety from acetyl-CoA (Ac-CoA) to the α-amino group of a nascent polypeptide. Here, we report the first global study of Nt-acetylation in response to changes in nutrient availability in S. cerevisiae. Despite major fluctuations in Ac-CoA and histone acetylation levels, our study reveals that the steady-state levels of protein Nt-acetylation remains largely unaffected by changes in cellular metabolism. Accordingly, Ac-CoA does not appear to act as a master switch for protein Nt-acetylation. Interestingly however, we identified two distinct sets of N-termini that are differentially Nt-acetylated following nutrient starvation. The first set of proteins, enriched for annotated N-termini, generally displayed an increased Nt-acetylation in stationary phase compared to exponential growth phase, despite a significant reduction in Ac-CoA levels. In contrast, the second set of proteins, enriched for alternative non-annotated N-termini (i.e. N-terminal proteoforms), generally became less acetylated in stationary phase. In particular, the degree of Nt-acetylation of Pcl8, a negative regulator of glycogen biosynthesis and two components of the pre-ribosome complex (Rsa3 and Rpl7a) increased during starvation. Moreover, the levels of these proteins were regulated by both starvation and the presence of NatA activity. Overall, our data provide the first proteome-wide survey on metabolic regulation of Nt-acetylation, and propose Nt-acetylation-mediated steering of metabolism and ribosome biogenesis.
2018-09-07 | PXD004326 | Pride
Project description:SMAC/DIABLO and HTRA2 are mitochondrial proteins whose N-termina sequences, known as inhibitor of apoptosis binding motifs (IBMs), bind and activate ubiquitin ligases knwon as inhibitor of apoptosis proteins (IAPs), unleashing a cell´s poteintial.IBMs comprise a 4-residue, loose consensus sequence, and binding to IAPs requires an unmodified N-terminus. Closely related, IBM-like N-termini, are present in approximately 5% of human proteins. We show that suppression of the N-alpha-acetytransferase NatA truns these cryptic IBM-like sequences into very efficient IAP binders in cell lysates and in vitro, and ultimately also triggers apoptosis. Thus, N-terminal acetylation of IBM-like motifs in NatA substrates shields them from IAPs. This previously unrecognized relatonship suggests that N-terminal acetylation is generally protective against protein degradation in human cells. It also identifies IAPs as agents of a general quality control mechanism targeting unacetylated rogues in metazoans
2021-09-09 | PXD021815 | Pride
Project description:N-terminal acetylation of the Set1-COMPASS fine-tunes H3K4 methylation patterns
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