PXD045533-1

PXD045533 is an original dataset announced via ProteomeXchange.

Title	Shared and Distinct Mechanisms of UBA1 Inactivation Across Different Diseases
Description	UBA1 initiates most cellular ubiquitin signaling by activating and transferring ubiquitin to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause a severe inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked autoinflammatory, somatic) syndrome. Despite extensive investigation into the clinical manifestations of this lethal disease, little is known about the underlying molecular mechanisms. Here, we systematically dissect VEXAS-causing mutations in UBA1 to better understand disease pathogenesis. We find that only UBA1 p.Met41 mutations alter cytoplasmic isoform expression, while the remaining mutations reduce catalytic function of both cytoplasmic and nuclear isoforms by diverse mechanisms, including defective ubiquitin adenylation, reduced thioesterification, and aberrant oxyester formation. Strikingly, most non-p.Met41 mutations prominently affect transthioesterification, revealing ubiquitin conjugation to cytoplasmic E2 enzymes as a shared property of pathogenesis amongst different VEXAS syndrome genotypes.
HostingRepository	MassIVE
AnnounceDate	2024-01-12
AnnouncementXML	Submission_2024-01-12_13:47:10.022.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yan Wang
SpeciesList	scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationList	GG
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-20 14:21:46	ID requested
⏵ 1	2024-01-12 13:47:10	announced

no publication

submitter keyword: oxyester, UBA1, Ubiquitylation, VEXAS syndrome, E2 enzyme

Yan Wang
contact affiliation	NIH/NIDCR
contact email	wangyan2@nih.gov
lab head
Yan Wang
contact affiliation	NIH
contact email	yan.wang2@nih.gov
dataset submitter

MassIVE dataset URI

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