PXD070265

PXD070265 is an original dataset announced via ProteomeXchange.

Title	CELF2 Promotes Tau Exon 10 Inclusion Via Hinge Domain-Mediated Nuclear Condensation
Description	Alternative splicing is a fundamental process that contributes to the functional diversity and complexity of proteins. The regulation of each alternative splicing event involves the coordinated action of multiple RNA-binding proteins, creating a diverse array of alternatively spliced products. Dysregulation of alternative splicing is associated with various diseases, including neurodegeneration. Here we demonstrate that CELF2 binds mRNAs associated with neurodegenerative diseases, with a specific interaction observed in the intron adjacent to exon 10 on tau mRNA. Loss of CELF2 in the mouse brain results in a decreased inclusion of tau exon 10, leading to a reduced 4R:3R ratio. The hinge domain of CELF2 possesses an intrinsically disordered region (IDR), which mediates CELF2 condensation. The IDR is required for CELF2 activity in promoting tau exon 10 inclusion and can be functionally replaced by the IDRs of FUS or TAF15. With CRISPR-based imaging, we showed that CELF2 condensates colocalize with tau RNA. Using TurboID, we identified proteins that interact with CELF2 through its IDR. CELF2 co-condensates with NOVA2 and SFPQ, which coordinate with CELF2 to regulate the alternative splicing of Tau exon 10. We found that a conserved negatively charged residue within the IDR (D388) was critical for CELF2 condensate formation, its interactions with NOVA2 and SFPQ, and its function in regulating tau exon 10 splicing. Finally, we revealed that CELF2 condensation capacity is associated with 4R tau expression in vivo, impacting locomotor and cognitive function. Our data suggest that CELF2 regulates tau alternative splicing by forming condensates through its IDR with other splicing factors, and that the composition of the proteins within the condensates determines the balance of tau isoforms to impact neuronal function.
HostingRepository	PRIDE
AnnounceDate	2026-07-28
AnnouncementXML	Submission_2026-07-28_14:22:07.363.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD070265
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Zhao Zhang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-11-03 18:33:58	ID requested
⏵ 1	2026-07-28 14:22:07	announced

10.6019/PXD070265;

submitter keyword: None

Lizhen Chen
contact affiliation	Barshop Institute for Longevity and Aging Studies, Department of Cell Systems and Anatomy, UT San Antonio
contact email	ChenL7@uthscsa.edu
lab head
Zhao Zhang
contact affiliation	Department of Molecular Medicine, UT San Antonio
contact email	zhangz3@uthscsa.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD070265
     1. Label: PRIDE project
     2. Name: CELF2 Promotes Tau Exon 10 Inclusion Via Hinge Domain-Mediated Nuclear Condensation