Dataset Information

Shared and Distinct Mechanisms of UBA1 Inactivation Across Different Diseases

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Yan Wang

PROVIDER: MSV000092914 | MassIVE |

SECONDARY ACCESSION(S): PXD045533

REPOSITORIES: MassIVE

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Shared and distinct mechanisms of UBA1 inactivation across different diseases.

Collins Jason C JC Magaziner Samuel J SJ English Maya M Hassan Bakar B Chen Xiang X Balanda Nicholas N Anderson Meghan M Lam Athena A Fernandez-Pol Sebastian S Kwong Bernice B Greenberg Peter L PL Terrier Benjamin B Likhite Mary E ME Kosmider Olivier O Wang Yan Y Samara Nadine L NL Walters Kylie J KJ Beck David B DB Werner Achim A

The EMBO journal 20240215 10

Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers ubiquitin to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little is known about the underlying molecular mechanisms. Here, by dissecting VEXAS-causing UBA1 mutations, we discovered that p.Met41 mutations a ...[more]

PMID: 38360993

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