PXD030889-1

PXD030889 is an original dataset announced via ProteomeXchange.

Title	Translation rescue by targeting Ppp1r15a upstream open reading frame in vivo
Description	The eIF2 initiation complex is central to maintaining a functional translation machinery. Extreme stress such as life-threatening sepsis exposes vulnerabilities in this tightly regulated system, resulting in an imbalance between the opposing actions of kinases and phosphatases on the main regulatory subunit eIF2α. Here, we report that translation shutdown is a hallmark of established sepsis-induced kidney injury brought about by excessive eIF2α phosphorylation and sustained by blunted expression of the counterregulatory phosphatase subunit Ppp1r15a. We determined that the blunted Ppp1r15a expression persists because of the presence of an upstream open reading frame (uORF). Overcoming this barrier with genetic approaches enabled the depression of Ppp1r15a, salvaged translation and improved kidney function in an endotoxemia model. We also found that the loss of this uORF has broad effects on the composition and phosphorylation status of the immunopeptidome that extended beyond the eIF2α axis. Collectively, our findings define the breadth and potency of the highly conserved Ppp1r15a uORF and provide a paradigm for the design of uORF-based translation rheostat strategies. The ability to accurately control the dynamics of translation during sepsis will open new paths for the development of therapies at codon level precision.
HostingRepository	PRIDE
AnnounceDate	2022-09-28
AnnouncementXML	Submission_2022-09-28_08:13:15.975.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD030889
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Emma Doud
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; TMT6plex reporter fragment; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse; Orbitrap Exploris 480; Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2022-01-11 01:34:17	ID requested
⏵ 1	2022-09-28 08:13:16	announced

Dataset with its publication pending

submitter keyword: eIF2 initation complex, translation, Ppp1r15a, uORF, phoshporylation, kidney, LCMSMSi

Takashi Hato, MD
contact affiliation	IU School of Medicine, Department of Medicine, Division of Nephrology
contact email	thato@iu.edu
lab head
Emma Doud
contact affiliation	Indiana University School of Medicine
contact email	edoud@iu.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD030889
     1. Label: PRIDE project
     2. Name: Translation rescue by targeting Ppp1r15a upstream open reading frame in vivo