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| Item Type: | Article |
|---|---|
| Title: | Astrocytic-OTUD7B ameliorates murine experimental autoimmune encephalomyelitis by stabilizing glial fibrillary acidic protein and preventing inflammation |
| Creators Name: | Harit, Kunjan, Yi, Wenjing, Jeron, Andreas, Schmidt, Jakob, Beckervordersandforth, Ruth, Wyler, Emanuel, Manukyan, Artür, Deckert, Martina, Radbruch, Helena, Conrad, Thomas, Altmüller, Janine, Landthaler, Markus, Wang, Xu, Nishanth, Gopala and Schlüter, Dirk |
| Abstract: | Astrocytes are central to the pathogenesis of multiple sclerosis (MS); however, their regulation by post-translational ubiquitination and deubiquitination is unresolved. This study shows that the deubiquitinating enzyme OTUD7B in astrocytes protects against murine experimental autoimmune encephalomyelitis (EAE), a model of MS, by limiting neuroinflammation. RNA-sequencing of isolated astrocytes and spatial transcriptomics show that in EAE, OTUD7B downregulates chemokine expression in astrocytes of inflammatory lesions, which is associated with reduced recruitment of encephalitogenic CD4(+) T cells. Furthermore, OTUD7B is necessary for glial fibrillary acidic protein (GFAP) expression of astrocytes bordering inflammatory lesions. Mechanistically, OTUD7B (i) restricts TNF-induced chemokine production of astrocytes by sequential K63- and K48-deubiquitination of RIPK1, which limits NF-κB and MAPK activation and (ii) enables GFAP protein expression by supporting GFAP mRNA expression and preventing its proteasomal degradation through K48-deubiquitination of GFAP. This dual action on TNF signaling and GFAP identifies OTUD7B as a central inhibitor of astrocyte-mediated inflammation. |
| Keywords: | Astrocytes, CD4-Positive T-Lymphocytes, Deubiquitinating Enzymes, Experimental Autoimmune Encephalomyelitis, Glial Fibrillary Acidic Protein, Inbred C57BL Mice, Inflammation, Multiple Sclerosis, NF-Kappa B, Receptor-Interacting Protein Serine-Threonine Kinases, Tumor Necrosis Factor-Alpha, Ubiquitination, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 16 |
| Number: | 1 |
| Page Range: | 9279 |
| Date: | 20 October 2025 |
| Official Publication: | https://doi.org/10.1038/s41467-025-65093-4 |
| PubMed: | View item in PubMed |
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