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Asparagine hydroxylation is likely to be a reversible post-translational modification

ABSTRACT: Amino acid hydroxylation is a common post-translational modification, which generally regulates protein interactions or adds a functional group that can be further modified. Such hydroxylation is currently considered irreversible, necessitating the degradation and re-synthesis of the entire protein to reset the modification. Here we present evidence that the cellular machinery can reverse FIH-mediated asparagine hydroxylation on intact proteins. These data suggest that asparagine hydroxylation is a flexible and dynamic post-translational modification akin to modifications involved in regulating signalling networks, such as phosphorylation, methylation and ubiquitylation.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Hordeum Vulgare (barley)

TISSUE(S): Epithelial Cell

SUBMITTER: Alex von kriegsheim

LAB HEAD: Alex von Kriegsheim

PROVIDER: PXD013116 | Pride | 2020-03-23

REPOSITORIES: Pride

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			Action	DRS
	01_wash.raw	Raw
	02_TNKs-control.raw	Raw
	02_sample-1.raw	Raw
	02_sample-1_20200204095339.raw	Raw
	03_TNKs-control-2.raw	Raw

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Publications

Asparagine Hydroxylation is a Reversible Post-translational Modification.

Rodriguez Javier J Haydinger Cameron D CD Peet Daniel J DJ Nguyen Lan K LK von Kriegsheim Alex A

Molecular & cellular proteomics : MCP 20200805 11

Amino acid hydroxylation is a common post-translational modification, which generally regulates protein interactions or adds a functional group that can be further modified. Such hydroxylation is currently considered irreversible, necessitating the degradation and re-synthesis of the entire protein to reset the modification. Here we present evidence that the cellular machinery can reverse FIH-mediated asparagine hydroxylation on intact proteins. These data suggest that asparagine hydroxylation i ...[more]

PMID: 32759169

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PHD3 and FIH substrates cluster in distinct signalling pathways

Project description:Amino acid hydroxylation is a common post-translational modification which regulates intra and inter-molecular protein-protein interactions. The modifications are regulated by a family of 2-oxoglutarate (2OG) dependent enzymes and although the biochemistry is well understood, until now only a few substrates have been described for these enzymes. We present here a sensitive method which specifically enriches and identifies hydroxylase substrates. We screened for substrates of PHD3 and FIH, a proline and asparagine hydroxylase respectively which regulate the HIF-mediated hypoxic response and were able to confirm known substrates as well as identifying hundreds of potential novel ones. Enrichment analysis revealed that the substrates of both hydroxylases cluster in the same pathways but frequently modify different nodes of these networks. We confirm that two proteins identified in this screen, MAPK6 and RIPK4, are indeed hydroxylated in a FIH or PHD3 dependent mechanism and explore the biological consequences of the hydroxylation.

2016-03-30 | PXD001085 | Pride

Asparagine hydroxylation of the UBA domain in Cezanne (OTUD7B)

Project description:by DUBs need to be tightly controlled. Here, we identify asparagine hydroxylation as a novel posttranslational modification involved in the regulation of Cezanne (OTUD7B), a DUB that controls key cellular functions and signaling pathways. We demonstrate that Cezanne is a substrate for FIH1- and oxygen-dependent asparagine hydroxylation. FIH1 modifies Asn35 within the uncharacterized N-terminal ubiquitin-associated (UBA)-like domain of Cezanne (UBACez), which lacks conserved UBA domain properties. We show for the first time that UBACez binds Lys11-, Lys48-, Lys63- and Met1-linked ubiquitin chains in vitro, and thereby establish UBACez as a functional ubiquitin-binding domain. We reveal that interaction of UBACez with ubiquitin is mediated via a non-canonical surface, and that hydroxylation of Asn35 inhibits ubiquitin binding. Recently, it has been suggested that recruitment of Cezanne to specific target proteins depends on UBACez. Our data show that UBACez can indeed fulfil this role as regulatory domain by binding differently linked ubiquitin chains and that this interaction with ubiquitin, and thus modified substrates, can be modulated by asparagine hydroxylation.

2020-01-24 | PXD015216 | Pride

Asparagine availability controlsgerminal centre B cell homeostasis

Project description:Germinal centre (GC) B cells proliferate at some of the highest rates of any mammalian cell. Yet the metabolic processes which enable this are poorly understood. We performed integrated metabolomic and transcriptomic profiling of GC B cells, and found that asparagine metabolism is highly upregulated. Asparagine is conditionally essential to B cells, and its synthetic enzyme, asparagine synthetase (ASNS) is markedly upregulated following their activation, through the integrated stress response sensor general control non-derepressible 2 (GCN2). When Asns is deleted, B cell survival in low asparagine conditions is severely impaired. Using stable isotope tracing, we found that metabolic adaptation to the absence of asparagine requires ASNS, and that the synthesis of nucleotides is particularly sensitive to asparagine deprivation. Conditional deletion of Asns in B cells selectively impairs GC formation, associated with a reduction in RNA synthesis rates. Finally, removal of environmental asparagine by asparaginase was found to also severely compromise the GC reaction.

2024-04-03 | GSE228845 | GEO

FIH regulates cellular metabolism through hydroxylation of the deubiquitinase OTUB1.

Project description:The asparagine hydroxylase, factor inhibiting HIF (FIH) confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing, ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by endogenous FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, mutant OTUB1 (lacking the hydroxylation site) impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH, and propose that this provides new insight into the regulation of cellular energy metabolism during hypoxia.

2016-01-11 | PXD002103 | Pride

Gene expression profiling of leukemia cells following asparagine depletion

Project description:We will report the gene expression changes following asparagine depletion in human ALL cell line, RS4;11

2019-08-06 | GSE135420 | GEO

Asparagine starvation on histone methylation and gene expression

Project description:We are determining the impact of asparagine starvation on histone H3K4 trimethylation deposition across the genome and how they may affect the gene expression.

2022-06-16 | GSE206112 | GEO

Asparagine availability governs metastasis in a model of breast cancer

Project description:Single - cell profiling of patient tumours and of mouse models is revealing that many cancers are constituted of communities of genetically and phenotypically distinct clonal lineages 1 - 12. A functional model of breast cancer heterogeneity revealed that clonal sub - populations proficient at generating circulating tumour cells were not equally capable of forming metastases at secondary sites 13. A combination of differential expression and focused in vitro and in vivo RNAi screens revealed candidate drivers of metastasis discriminating these clones, which were then evaluated in gene expression datasets from breast cancer patients. Among these, Asparagine Synthetase (Asns) expression in a patient's primary tumour was most strongly correlated with later metastatic relapse. Silencing of Asns reduced both metastatic potential in vivo and invasive potential in vitro. Conversely, increasing the availability of extracellular asparagine increased the invasive potential of mouse and human breast cancer cells, and enforced Asns expression promoted metastasis. Decreasing asparagine availability in mice by treatment with L-asparaginase or even by dietary restriction strongly reduced metastasis from orthotopic tumours. Asparagine availability varies betwe en tissues, potentially explaining selective effects on particular steps of tumor progression. Asparagine limitation reduced the production of proteins that promote the epithelial to mesenchymal transition, providing one potential mechanism for how the availability of a single amino acid could regulate metastatic progression.

2018-02-08 | GSE107109 | GEO

Lack of electron acceptors contributes to redox stress and growth arrest in asparagine-starved sarcoma cells

Project description:Adequate availability of the non-essential amino acid asparagine is necessary to support growth and survival of sarcoma cells. The three top pathways enriched among transcripts upregulated in asparagine-depleted cells included ribosome, aminoacyl tRNA biosynthesis and oxidative phosphorylation.

2022-06-20 | GSE153991 | GEO

Asparagine availability controlsgerminal centre B cell homeostasis

Project description:Asparagine availability controlsgerminal centre B cell homeostasis

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Molecular effects of ISRIB during asparagine deprivation

Project description:Molecular effects of ISRIB during asparagine deprivation

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