PXD073870

PXD073870 is an original dataset announced via ProteomeXchange.

Title	YTHDC1 functions as a molecular chaperone to suppress ALS-Linked hnRNPA1 mutants from aggregation
Description	Proteostasis failure underlies many neurodegenerative disorders (NDs), yet ATP-independent chaperone mechanisms in NDs remain incompletely defined. Here, we identify the N6-methyladenosine (m6A) binding protein YTHDC1 as an ATP-independent molecular chaperone whose activity is mediated by a highly acidic polyD/E segment. We demonstrate that YTHDC1 prevents heat-induced misfolding and aggregation, unfolds kinetically trapped substrates, and resolubilizes pre-formed aggregates. Depletion polyD/E abolishes these activities and reduces condensate fluidity. The chaperone function of YTHDC1 is independent of m6A recognition, as YTHDC1 aromatic-cage mutants retain the chaperone activities. We identify that hnRNPA1, an RNA binding protein, is one of the clients of YTHDC1. Focusing on the ALS-linked hnRNPA1, YTHDC1 maintains liquid-like condensates, delays fibrillization of disease mutants, and limits stress-granule sequestration, thereby preserving its normal cellular function and mitigating synaptic atrophy elicited by pathological hnRNPA1 in primary neurons. These findings reveal a novel function of YTHDC1 in proteostasis and suggest that enhancing its chaperone activity could offer a promising therapeutic strategy for counteracting the effects of protein aggregation in NDs.
HostingRepository	PRIDE
AnnounceDate	2026-08-22
AnnouncementXML	Submission_2026-08-21_19:38:12.594.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kang Ren
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue
Instrument	timsTOF HT; maXis

Revision	Datetime	Status	ChangeLog Entry
0	2026-01-31 00:52:53	ID requested
⏵ 1	2026-08-21 19:38:13	announced

10.1038/S41467-026-77016-Y;

submitter keyword: Phosphoproteomics,YTHDC1,hnRNPA1, HEK293T,SY5Y, LC-MS/MS

Liangqian Huang
contact affiliation	Institute of Modern Biology, Nanjing University, Nanjing 210008, Jiangsu, China
contact email	lqhuang@nju.edu.cn
lab head
Kang Ren
contact affiliation	Institute of Modern Biology, Nanjing University, Nanjing 210008, Jiangsu, China
contact email	602023960013@smail.nju.edu.cn
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/08/PXD073870

PRIDE project URI

• PRIDE
  1. PXD073870
     1. Label: PRIDE project
     2. Name: YTHDC1 functions as a molecular chaperone to suppress ALS-Linked hnRNPA1 mutants from aggregation