PXD028744

PXD028744 is an original dataset announced via ProteomeXchange.

Title	Halofuginone, a tRNA-synthetase inhibitor, decreases bulk protein synthesis independently of the integrated stress response
Description	The integrated stress response (ISR), a vital homeostatic pathway, is an emerging therapeutic target for a broad range of clinical indications. Halofuginone (HF) is a phase 2 clinical compound that induces the ISR by inhibiting the glutamyl-prolyl-tRNA synthetase (EPRS). Here we report that although HF induces the predicted canonical ISR adaptations consisting of attenuation of protein synthesis and gene expression reprogramming, the former surprisingly occurs independently of GCN2 and eIF2 phosphorylation. Proline supplementation rescues the observed HF-induced changes indicating that they result from an on-target effect due to inhibition of EPRS. We find that attenuation of translation initiation through GCN2-to-eIF2 signaling is not robust enough to prevent translation elongation defects caused by HF. Exploiting this vulnerability, we show that cancer cells presenting an increased proline dependency are sensitized to HF. This work provides novel insights on ISR signaling and a molecular framework to guide the targeted development of HF.
HostingRepository	PRIDE
AnnounceDate	2022-04-27
AnnouncementXML	Submission_2022-04-27_00:18:22.958.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sew Peak-Chew
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-09-24 11:01:23	ID requested
⏵ 1	2022-04-27 00:18:24	announced

Pitera AP, Szaruga M, Peak-Chew SY, Wingett SW, Bertolotti A, Cellular responses to halofuginone reveal a vulnerability of the GCN2 branch of the integrated stress response. EMBO J, 41(11):e109985(2022) [pubmed]

submitter keyword: Integrated stress response, stress responses, translation, GCN2, tRNA synthetase

Anne Bertolotti
contact affiliation	MRC_Laboratory of Molecular Biology Neurobiology Division
contact email	aberto@mrc-lmb.cam.ac.uk
lab head
Sew Peak-Chew
contact affiliation	MRC-LMB
contact email	spc@mrc-lmb.cam.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD028744
     1. Label: PRIDE project
     2. Name: Halofuginone, a tRNA-synthetase inhibitor, decreases bulk protein synthesis independently of the integrated stress response