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

Author

Listed:
  • Kunjan Harit

    (Hannover Medical School)

  • Wenjing Yi

    (Hannover Medical School)

  • Andreas Jeron

    (Otto-von-Guericke University Magdeburg)

  • Jakob Schmidt

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Ruth Beckervordersandforth

    (Friedrich-Alexander-Universität Erlangen-Nürnberg)

  • Emanuel Wyler

    (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Artür Manukyan

    (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Martina Deckert

    (University of Cologne)

  • Helena Radbruch

    (Institute of Neuropathology)

  • Thomas Conrad

    (Max Delbrück Center for Molecular Medicine)

  • Janine Altmüller

    (Max Delbrück Center for Molecular Medicine
    Berlin Institute of Health at Charité)

  • Markus Landthaler

    (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC)
    Humboldt-Universität zu Berlin)

  • Xu Wang

    (Hannover Medical School
    Wenzhou Medical University)

  • Gopala Nishanth

    (Hannover Medical School)

  • Dirk Schlüter

    (Hannover Medical School
    Hannover Medical School)

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.

Suggested Citation

  • Kunjan Harit & Wenjing Yi & Andreas Jeron & Jakob Schmidt & Ruth Beckervordersandforth & Emanuel Wyler & Artür Manukyan & Martina Deckert & Helena Radbruch & Thomas Conrad & Janine Altmüller & Markus , 2025. "Astrocytic-OTUD7B ameliorates murine experimental autoimmune encephalomyelitis by stabilizing glial fibrillary acidic protein and preventing inflammation," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65093-4
    DOI: 10.1038/s41467-025-65093-4
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    References listed on IDEAS

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    1. Ingrid E. Wertz & Karen M. O'Rourke & Honglin Zhou & Michael Eby & L. Aravind & Somasekar Seshagiri & Ping Wu & Christian Wiesmann & Rohan Baker & David L. Boone & Averil Ma & Eugene V. Koonin & Vishv, 2004. "De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling," Nature, Nature, vol. 430(7000), pages 694-699, August.
    2. Irene Molina-Gonzalez & Rebecca K. Holloway & Zoeb Jiwaji & Owen Dando & Sarah A. Kent & Katie Emelianova & Amy F. Lloyd & Lindsey H. Forbes & Ayisha Mahmood & Thomas Skripuletz & Viktoria Gudi & Jame, 2023. "Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
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