Astrocytic-OTUD7B ameliorates murine experimental autoimmune encephalomyelitis by stabilizing glial fibrillary acidic protein and preventing inflammation
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<sup>+</sup> 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.
Authors
- Helena Radbruch (ORCID: https://orcid.org/0000-0001-6941-3397)
- Gopala Nishanth
- Martina Deckert (ORCID: https://orcid.org/0000-0002-2468-0608)
- Kunjan Harit (ORCID: https://orcid.org/0009-0000-5089-4063)
- Janine Altmüller (ORCID: https://orcid.org/0000-0003-4372-1521)
- Ruth Beckervordersandforth (ORCID: https://orcid.org/0000-0002-3617-7567)
- Markus Landthaler (ORCID: https://orcid.org/0000-0002-1075-8734)
- Andreas Jeron
- Thomas Conrad (ORCID: https://orcid.org/0000-0001-5618-6295)
- Dirk Schlüter (ORCID: https://orcid.org/0000-0003-1478-3328)
- Wenjing Yi (ORCID: https://orcid.org/0000-0001-6192-6710)
- Emanuel Wyler (ORCID: https://orcid.org/0000-0002-9884-1806)
- Artür Manukyan (ORCID: https://orcid.org/0000-0002-0441-9517)
- Xu Wang (ORCID: https://orcid.org/0000-0001-8428-9339)
- Jakob Schmidt
Institutions
- University of Cologne (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Max Delbrück Center (DE)
- Wenzhou Medical University (CN)
- Medizinische Hochschule Hannover (DE)
- Humboldt-Universität zu Berlin (DE)
- Zhejiang Lab (CN)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- University Hospital Cologne (DE)
- Charité - Universitätsmedizin Berlin (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-20
- DOI
- https://doi.org/10.1038/s41467-025-65093-4
- Citations
- 1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Deutsche Forschungsgemeinschaft