MassIVE MSV000092914

Partial Public PXD045533

Shared and Distinct Mechanisms of UBA1 Inactivation Across Different Diseases

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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. [doi:10.25345/C5BZ61K2J] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: oxyester ; UBA1 ; Ubiquitylation ; VEXAS syndrome ; E2 enzyme

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Principal Investigators:
(in alphabetical order) 		Yan Wang, NIH/NIDCR, United States
Submitting User: Ywang16
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