Astrocytic-OTUD7B ameliorates murine experimental autoimmune encephalomyelitis by stabilizing glial fibrillary acidic protein and preventing inflammation
- Kunjan Harit
- Wenjing Yi
- Andreas Jeron
- Jakob Schmidt
- Ruth Beckervordersandforth
- Emanuel Wyler
- Artür Manukyan
- Martina Deckert
- Helena Radbruch
- Thomas Conrad
- Janine Altmüller
- Markus Landthaler
- Xu Wang
- Gopala Nishanth
- Dirk Schlüter
2025-10-20
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.