PXD063067-1

PXD063067 is an original dataset announced via ProteomeXchange.

Title	Dysregulation of protein homeostasis by mutant UBA1 in VEXAS syndrome
Description	VEXAS is a hematopoietic disorder characterized by hyperinflammation,high mortality, and mutations at methionine 41 (M41) in the E1 ubiquitin enzyme, UBA1. Here, we developed ahuman model of VEXAS by engineering the male THP1 cell line to express the UBA1-M41V mutation. We found that UBA1-M41V cells exhibit aberrant UBA1 isoform expression, increased vacuolization, and upregulation of the unfolded protein response, recapitulating features of VEXAS.Proteomic analyses revealed dysregulated ubiquitination and proteotoxic stress in UBA1-M41V cells, with alterations in inflammatory and stress-response pathways. UBA1-M41V cells were sensitive to genetic or pharmacological inhibition of E1 enzymes. Treatment with theE1 inhibitor TAK-243 preferentially suppressed colony formation of UBA1-M41V cells. Moreover,UBA1-M41V cells exhibited greater sensitivity to TAK-243 in competition assays and showed increased apoptosis. Interestingly, TAK-243 preferentially inhibited UBA6 activity over UBA1 ,suggesting that UBA6 may compensate for UBA1 dysfunction. Targeting UBA6 using shRNA orthe UBA6-specific inhibitor phytic acid further revealed an acquired dependency on UBA6 inUBA1-M41V cells. Phytic acid impaired UBA1-M41V cells while sparing WT cells. Together, these findings establish a novel human model of VEXAS, identify key roles for UBA1 and UBA6, and demonstrate that UBA6 inhibition represents a therapeutic strategy for selectively targeting UBA1 mutant clones.
HostingRepository	PRIDE
AnnounceDate	2025-08-04
AnnouncementXML	Submission_2025-08-03_16:09:45.869.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Courtnee Clough
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-17 06:53:24	ID requested
⏵ 1	2025-08-03 16:09:46	announced

10.1038/s41375-025-02671-x;

Clough CA, Cunningham C, Philbrook SY, Hueneman KM, Sampson AM, Choi K, Greis KD, Starczynowski D, Characterization of E1 enzyme dependencies in mutant-UBA1 human cells reveals UBA6 as a novel therapeutic target in VEXAS syndrome. Leukemia, 39(8):1997-2009(2025) [pubmed]

submitter keyword: Human, VEXAS

Daniel Starczynowski
contact affiliation	EHCB, Cincinnati Children's Hospital Medical Center, Cincinnati, OH,USA
contact email	daniel.starczynowski@cchmc.org
lab head
Courtnee Clough
contact affiliation	Cincinnati Children's Hospital Medical Center
contact email	courtnee.clough@cchmc.org
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/2025/08/PXD063067

PRIDE project URI

• PRIDE
  1. PXD063067
     1. Label: PRIDE project
     2. Name: Dysregulation of protein homeostasis by mutant UBA1 in VEXAS syndrome