Astrocytic-OTUD7B ameliorates murine experimental autoimmune encephalomyelitis by stabilizing glial fibrillary acidic protein and preventing inflammation

Harit K, Yi W, Jeron A, Schmidt J, Beckervordersandforth R, Wyler E, Manukyan A, Deckert M, Radbruch H, Conrad T, Altmüller J, Landthaler M, Wang X, Nishanth G, Schlüter D (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 16

Article Number: 9279

Journal Issue: 1

DOI: 10.1038/s41467-025-65093-4

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.

Authors with CRIS profile

Ruth Beckervordersandforth-Bonk Professur für Molekulare Neuropathologie (Heisenberg-Professur)

Involved external institutions

Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Otto-von-Guericke-Universität Magdeburg DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE) Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft / Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) DE Germany (DE)

How to cite

APA:

Harit, K., Yi, W., Jeron, A., Schmidt, J., Beckervordersandforth, R., Wyler, E.,... Schlüter, D. (2025). Astrocytic-OTUD7B ameliorates murine experimental autoimmune encephalomyelitis by stabilizing glial fibrillary acidic protein and preventing inflammation. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-65093-4

MLA:

Harit, Kunjan, et al. "Astrocytic-OTUD7B ameliorates murine experimental autoimmune encephalomyelitis by stabilizing glial fibrillary acidic protein and preventing inflammation." Nature Communications 16.1 (2025).

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