PXD045774

PXD045774 is an original dataset announced via ProteomeXchange.

Title	Chemical proteomics reveals that the anticancer drug everolimus affects ubiquitin-proteasome system
Description	Rapamycin is a natural antifungal, immunosuppressive, and antiproliferative compound allosterically inhibiting mTOR complex 1. The ubiquitin-proteasome system (UPS) responsible for protein turnover is usually not listed among the pathways affected by mTOR signaling; however, a number of reports indicated the interplay between UPS and mTOR. It is also reported that rapamycin and analogs can allosterically inhibit the proteasome itself. We studied the molecular effect of rapamycin and its analogs (rapalogs), everolimus, and temsirolimus by expression chemical proteomics on A549 cell line. The analysis revealed that the cellular response to everolimus differs dramatically from that of rapamycin and temsirolimus. In cluster analysis the effect of everolimus was similar to that of bortezomib, a well-established proteasome inhibitor. UPS-related pathways were enriched in the cluster of proteins specifically up-regulated upon everolimus and bortezomib treatments, suggesting that both compounds have similar proteasome inhibition effects. In particular, the total amount of ubiquitin was significantly elevated in the samples treated with everolimus and bortezomib, and the analysis of the polyubiquitination patterns revealed elevated intensities of the ubiquitin peptide with a GG modification at K48 residue, consistent with a bottleneck in the proteasomal protein degradation. Moreover, everolimus treatment resulted in both ubiquitin phosphorylation and a significant amount of semi-tryptic peptides illustrating the induction of protease activity. These observations suggest that everolimus affects the ubiquitin-proteasome system in a unique way and its mechanism of action is strikingly different from that of its close chemical analogs, rapamycin and temsirolimus.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:28:53.488.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lev Levitsky
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-28 07:07:57	ID requested
1	2024-02-08 17:52:43	announced
⏵ 2	2024-10-22 06:28:53	announced	2024-10-22: Updated project metadata.

10.1021/ACSPTSCI.3C00316;

submitter keyword: ubiquitin-proteasome system, expression proteomics, everolimus, ubiquitination, rapamycin, diglycine modification, semi-tryptic peptides,drug treatment, cell line

Mikhail Gorshkov
contact affiliation	INEPCP FRC CP RAS
contact email	mike.gorshkov@gmail.com
lab head
Lev Levitsky
contact affiliation	INEPCP RAS
contact email	lev.levitsky@phystech.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD045774
     1. Label: PRIDE project
     2. Name: Chemical proteomics reveals that the anticancer drug everolimus affects ubiquitin-proteasome system