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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: |
Harit, Kunjan, Yi, Wenjing, Jeron, Andreas, Schmidt, Jakob, Beckervordersandforth, Ruth  ORCID: https://orcid.org/0000-0002-3617-7567, Wyler, Emanuel ORCID: https://orcid.org/0000-0002-9884-1806, Manukyan, Artür ORCID: https://orcid.org/0000-0002-0441-9517, Deckert, Martina, Radbruch, Helena ORCID: https://orcid.org/0000-0001-6941-3397, Conrad, Thomas ORCID: https://orcid.org/0000-0001-5618-6295, Altmüller, Janine ORCID: https://orcid.org/0000-0003-4372-1521, Landthaler, Markus ORCID: https://orcid.org/0000-0002-1075-8734, Wang, Xu ORCID: https://orcid.org/0000-0001-8428-9339, Nishanth, Gopala ORCID: https://orcid.org/0000-0002-7280-5663 and Schlüter, Dirk ORCID: https://orcid.org/0000-0003-1478-3328
|
| 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 |
| Related to: |
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