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EMBO Rep. 2018 Apr;19(4). pii: e44754. doi: 10.15252/embr.201744754. Epub 2018 Feb 21.

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

Author information

1
Institute of Molecular Biology (IMB), Mainz, Germany.
2
Department of Medicine, Hematology/Oncology, Goethe University School of Medicine, Frankfurt, Germany swagner@med.uni-frankfurt.de p.beli@imb-mainz.de.
3
Institute of Molecular Biology (IMB), Mainz, Germany swagner@med.uni-frankfurt.de p.beli@imb-mainz.de.

Abstract

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.

KEYWORDS:

VCP ; HUWE1; K6‐linked ubiquitylation; c‐Myc; ubiquitin remnant profiling

PMID:
29467282
PMCID:
PMC5891417
DOI:
10.15252/embr.201744754
[Indexed for MEDLINE]
Free PMC Article

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