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Proteomic profiling of VCP substrates links VCP to K6‐linked ubiquitylation and c‐Myc function
Author(s) -
Heidelberger Jan B,
Voigt Andrea,
Borisova Marina E,
Petrosino Giuseppe,
Ruf Stefanie,
Wagner Sebastian A,
Beli Petra
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201744754
Subject(s) - ubiquitin , profiling (computer programming) , microbiology and biotechnology , deubiquitinating enzyme , computational biology , function (biology) , biology , chemistry , genetics , gene , computer science , operating system
Valosin‐containing protein (VCP) is an evolutionarily conserved ubiquitin‐dependent ATP ase 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 HUWE 1. 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.