| Accession | PRJCA025038 | |||||||||||||||
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| Title | Disturbing cellular homeostasis by loss of ubiquitin-activation enzyme UBA1 in neutrophils induces non-lethal VEXAS-like autoinflammatory diseases in mice | |||||||||||||||
| Relevance | Medical | |||||||||||||||
| Data types |
Transcriptome or Gene expression
Genome sequencing and assembly Raw sequence reads Single cell sequencing |
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| Organisms | Mus musculus | |||||||||||||||
| Description | VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome was a recently described haemato-rheumatoid disease with somatic mutations in UBA1 and loss of UBA1 cytoplasm isoform at the hematopoietic stem cells (HSCs). The autoinflammatory disease induces high mortality with a prevalence about 1: 4,000 for adult males older than 50 years. The clinical symptoms include myelodysplastic syndrome-like blood disorders, dermatitis and polychondritis. A mouse model for VEXAS is lacking and the disease-driving cell-type is unknown. Here we report that loss of Uba1 in various mouse hematopoietic cell types results in pleiotropic consequences and that the NECre-CKO mutants with loss of Uba1 in neutrophils induces non-lethal VEXAS-like symptoms. Depletion of Uba1 in HSCs induce a quick and large fraction hematopoietic cell death while depletion of Uba1 in B or T lymphoid cells, or in megakaryocytes also induce corresponsive cell death but the mutants appear normal. Depletion of Uba1 in monocytes and neutrophils failed to induce cell death and the mutants are viable, but depletion of Uba1 in neutrophils manifest autoinflammatory symptoms including increased counts of white blood cell and neutrophils percentage, splenomegaly, dermatosis but no polychondritis. Neutrophil-specific depletion of Uba1 and the encoded protein in NECre-CKO was validated experimentally and the mutant neutrophils manifest disturbed cellular hemostasis including reduced ubiquitylation, enhanced neutrophil extracellular trap formation and necroptosis. In conclusion, we report the pleiotropic effects with loss of Uba1 in blood cells and a first VEXAS-like mouse model, which assists understanding and treatment of the newly identified auto-inflammatory syndrome prevalent for aged men. | |||||||||||||||
| Sample scope | Multiisolate | |||||||||||||||
| Release date | 2025-08-08 | |||||||||||||||
| Publication |
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| Submitter | Zhigang Cai (us36zcai@tmu.edu.cn) | |||||||||||||||
| Organization | Tianjin Medical University | |||||||||||||||
| Submission date | 2024-04-08 |