Imipridone Anticancer Compounds Ectopically Activate the ClpP Protease and Represent a New Scaffold for Antibiotic Development.
Anti-Bacterial Agents
/ pharmacology
Antineoplastic Agents
/ pharmacology
Bacillus subtilis
/ drug effects
Binding Sites
Conserved Sequence
Depsipeptides
/ metabolism
Endopeptidase Clp
/ chemistry
Escherichia coli
/ drug effects
Escherichia coli Proteins
/ agonists
HEK293 Cells
Humans
Imidazoles
/ pharmacology
Metalloendopeptidases
/ metabolism
Protein Binding
Proteolysis
Pyridines
/ pharmacology
Pyrimidines
/ pharmacology
Rifampin
/ pharmacology
Staphylococcus aureus
/ drug effects
AAA+ ATPase
CLPP
CRISPR screen
MIPEP
antibiotic
imipridone
mitochondrion
proteolysis
proteome
synergism
Journal
Genetics
ISSN: 1943-2631
Titre abrégé: Genetics
Pays: United States
ID NLM: 0374636
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
07
11
2019
accepted:
06
02
2020
pubmed:
26
2
2020
medline:
22
4
2021
entrez:
26
2
2020
Statut:
ppublish
Résumé
Systematic genetic interaction profiles can reveal the mechanisms-of-action of bioactive compounds. The imipridone ONC201, which is currently in cancer clinical trials, has been ascribed a variety of different targets. To investigate the genetic dependencies of imipridone action, we screened a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) knockout library in the presence of either ONC201 or its more potent analog ONC212. Loss of the mitochondrial matrix protease CLPP or the mitochondrial intermediate peptidase MIPEP conferred strong resistance to both compounds. Biochemical and surrogate genetic assays showed that impridones directly activate CLPP and that MIPEP is necessary for proteolytic maturation of CLPP into a catalytically competent form. Quantitative proteomic analysis of cells treated with ONC212 revealed degradation of many mitochondrial as well as nonmitochondrial proteins. Prompted by the conservation of ClpP from bacteria to humans, we found that the imipridones also activate ClpP from
Identifiants
pubmed: 32094149
pii: genetics.119.302851
doi: 10.1534/genetics.119.302851
pmc: PMC7153937
doi:
Substances chimiques
ADEP4 acyldepsipeptide
0
Anti-Bacterial Agents
0
Antineoplastic Agents
0
Depsipeptides
0
Escherichia coli Proteins
0
Imidazoles
0
Pyridines
0
Pyrimidines
0
TIC10 compound
9U35A31JAI
ClpP protease, E coli
EC 3.4.21.92
ClpP protein, human
EC 3.4.21.92
Endopeptidase Clp
EC 3.4.21.92
Metalloendopeptidases
EC 3.4.24.-
mitochondrial intermediate peptidase
EC 3.4.24.59
Rifampin
VJT6J7R4TR
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1103-1120Subventions
Organisme : CIHR
ID : FDN-167277
Pays : Canada
Organisme : CIHR
ID : FDN-148463
Pays : Canada
Informations de copyright
Copyright © 2020 Jacques et al.
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