PXD057806

PXD057806 is an original dataset announced via ProteomeXchange.

Title	Pooled overexpression screening identifies PIPPI as a novel microprotein involved in the ER stress response
Description	Microproteins encoded by short open reading frames (sORFs) of less than 100 codons have been predicted to constitute a substantial fraction of the eukaryotic proteome. However, relevance and roles of the majority of microproteins remain undefined because only a small fraction of these intriguing cellular players have been in-depth characterized so far. Here we propose to use pooled overexpression screens of synthetic sORFs to overcome the challenge of elucidating which of the thousands of putative translated sORFs are biologically functional. As a proof-of-concept, we performed a phenotypic screen to identify sORFs protecting cells from treatment with the nucleotide analogue 6-thioguanine. With this approach, we identified two cytoprotective microproteins: altDDIT3 and PIPPI. PIPPI is encoded as part of the LC16a core duplicon, a highly duplicated region of the human genome, which is undergoing rapid positive selection in primates. Our data show that PIPPI is a novel component of the endoplasmic reticulum, where it fulfills its function by interacting and regulating the protein disulfide isomerase ERp44. Besides providing mechanistic insights on a new microprotein, this study highlights the power of using pooled overexpression screens to identify functional microproteins.
HostingRepository	PRIDE
AnnounceDate	2025-11-17
AnnouncementXML	Submission_2025-11-16_18:42:16.479.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Maximilian Hornisch
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-12 10:10:40	ID requested
⏵ 1	2025-11-16 18:42:17	announced

Lafranchi L, Raja GL, Arenas AM, Spinner A, Shrung KR, Hornisch M, Schlesinger D, Luzon CN, Brinkenstr, å, hle L, Shao R, Piazza I, Lehti, ö J, Branca RMM, Els, ӓ, sser SJ, Pooled overexpression screening identifies PIPPI as a novel microprotein involved in the ER stress response. Nucleic Acids Res, 53(20):(2025) [pubmed]

10.1093/nar/gkaf1072;

submitter keyword: microprotein

Ilaria Piazza
contact affiliation	Max Delbrück Center for Molecular Medicine in the Helmholtz Association; Berlin Institute of Medical Systems Biology (BIMSB)
contact email	ilaria.piazza@mdc-berlin.de
lab head
Maximilian Hornisch
contact affiliation	Max Delbrueck Centrum for Molecular Medicine
contact email	maximilian.hornisch@mdc-berlin.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD057806
     1. Label: PRIDE project
     2. Name: Pooled overexpression screening identifies PIPPI as a novel microprotein involved in the ER stress response