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Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function

ABSTRACT: Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function

OTHER RELATED OMICS DATASETS IN: PXD003936

PROVIDER: PRJNA419745 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6321901.fastq.gz	Fastqsanger.gz
	SRR6321902.fastq.gz	Fastqsanger.gz
	SRR6321903.fastq.gz	Fastqsanger.gz
	SRR6321904.fastq.gz	Fastqsanger.gz
	SRR6321905.fastq.gz	Fastqsanger.gz

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Similar Datasets

Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function

Project description:VCP is an evolutionary conserved ubiquitin-dependent ATPase that mediates the degradation of proteins through the ubiquitin-proteasome pathway. Despite the central role of VCP in the regulation of protein homeostasis, identity and nature of its cellular substrates remain poorly defined. Here, we combined chemical inhibition of VCP and quantitative ubiquitin remnant profiling to assess the effect of VCP inhibition on the ubiquitin-modified proteome and to probe the substrate spectrum of VCP in human cells. We demonstrate that inhibition of VCP perturbs cellular ubiquitylation and increases ubiquitylation of a different subset of proteins compared to proteasome inhibition. VCP inhibition globally upregulates K6-linked ubiquitylation that is dependent on the HECT-type ubiquitin E3 ligase HUWE1. We report ~450 putative VCP substrates, many of which function in nuclear processes, including gene expression, DNA repair and cell cycle. Moreover, we identify that VCP regulates the level and activity of the transcription factor c-Myc.

2018-02-08 | GSE107313 | GEO

Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function

2018-02-09 | PXD003936 | Pride

Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function.

Project description:Valosin-containing protein (VCP) is an evolutionarily conserved ubiquitin-dependent ATPase that mediates the degradation of proteins through the ubiquitin-proteasome pathway. Despite the central role of VCP in the regulation of protein homeostasis, identity and nature of its cellular substrates remain poorly defined. Here, we combined chemical inhibition of VCP and quantitative ubiquitin remnant profiling to assess the effect of VCP inhibition on the ubiquitin-modified proteome and to probe the substrate spectrum of VCP in human cells. We demonstrate that inhibition of VCP perturbs cellular ubiquitylation and increases ubiquitylation of a different subset of proteins compared to proteasome inhibition. VCP inhibition globally upregulates K6-linked ubiquitylation that is dependent on the HECT-type ubiquitin E3 ligase HUWE1. We report ~450 putative VCP substrates, many of which function in nuclear processes, including gene expression, DNA repair and cell cycle. Moreover, we identify that VCP regulates the level and activity of the transcription factor c-Myc.

| S-EPMC5891417 | biostudies-literature

Atypical K6-linked ubiquitylation marks toxic RNA-protein crosslinks induced by formaldehyde

Project description:Reactive aldehydes are produced during cellular metabolism and can accumulate in specific tissues particularly when aldehyde clearance mechanisms are impaired. Reactive aldehydes induce DNA-DNA and DNA-protein crosslinks (DPCs) that are repaired by different DNA repair pathways. Cellular toxicity of endogenous formaldehyde has been attributed to the damage of the genomic DNA and consequent inhibition of transcription. However, whether damage to other cellular macromolecules and interference with additional metabolic processes contributes to formaldehyde toxicity has not been investigated. We demonstrate that formaldehyde induces toxic RNA-protein crosslinks (RPCs) in mRNA that inhibit translation and induce a specific RPC stress response pathway that is characterized by linkage-specific ubiquitylation. RPCs in the mRNA are recognized by stalling ribosomes and marked by K6-linked ubiquitylation that promotes their clearance by the ubiquitin-dependent unfoldase VCP.

2023-09-01 | GSE225044 | GEO

K6-Linked Ubiquitylation Signals Reactive Aldehyde-Induced RNA-Protein Crosslink Resolution

Project description:Reactive aldehydes induce the formation of RNA-protein crosslinks (RPCs), RPCs in the mRNA stall the ribosome and inhibit translation, RPCs are K6-linked ubiqutylated by RBR-type E3 ligase RNF14, RPCs are resolved in a UBXN1-VCP/p97-dependent manner

2023-11-03 | GSE240625 | GEO

K6-Linked Ubiquitylation Marks Formaldehyde-Induced RNA–Protein Crosslinks for Resolution

Project description:Reactive aldehydes are produced by normal cellular metabolism or after alcohol consumption, and accumulate in human tissues if aldehyde clearance mechanisms are impaired. Their toxicity has been attributed to the damage they cause to genomic DNA and the subsequent inhibition of transcription and replication. However, whether interference with other cellular processes contributes to aldehyde toxicity has not been investigated. We demonstrate that formaldehyde induces RNA–protein crosslinks (RPCs) that stall the ribosome and inhibit translation in human cells. RPCs in the messenger RNA are recognized by the translating ribosomes, marked by atypical K6-linked ubiquitylation catalyzed by the RING-in-Between-RING E3 ligase RNF14, and subsequently resolved by the ubiquitin- and ATP-dependent unfoldase VCP. Our findings uncover an evolutionary conserved formaldehyde-induced stress response pathway that protects cells against RPC accumulation in the cytoplasm, and suggest that RPCs contribute to the cellular and tissue toxicity of reactive aldehydes.

2023-11-13 | PXD038655 | Pride

K6-Linked Ubiquitylation Signals Reactive Aldehyde-Induced RNA-Protein Crosslink Resolution

Project description:K6-Linked Ubiquitylation Signals Reactive Aldehyde-Induced RNA-Protein Crosslink Resolution

| PRJNA1004331 | ENA

Atypical K6-linked ubiquitylation marks toxic RNA-protein crosslinks induced by formaldehyde

Project description:Atypical K6-linked ubiquitylation marks toxic RNA-protein crosslinks induced by formaldehyde

| PRJNA933609 | ENA

Neuronal VCP loss of function recapitulates FTLD-TDP pathology

Project description:The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivated VCP in murine postnatal forebrain neurons (VCP cKO). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulated features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.

2021-06-16 | GSE178257 | GEO

RNAi knock down of VCP in human HeLa cells

Project description:Study of the effects of the VCP knockdown. VCP (p97, yeast cdc48) is a hexameric AAA ATPase involved in various cellular functions including degradation of proteins by the ubiquitin-proteasome system. We examine the consequences of the reduction of VCP levels after RNAi of VCP in HeLa cells. We find ~30 transcripts upregulated in a sequence independent manner. Those transcripts encode proteins involved in endoplasmic reticulum stress, apoptosis, and amino acid starvation.

2006-08-23 | E-MEXP-817 | biostudies-arrayexpress

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