Abstract |
Astrocytes are critical regulators of neuroinflammation in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Growing evidence indicates that ubiquitination of signaling molecules is an important cell-intrinsic mechanism governing astrocyte function during MS and EAE Here, we identified an upregulation of the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) in astrocytes during MS and EAE Mice with astrocyte-specific OTUB1 ablation developed more severe EAE due to increased leukocyte accumulation, proinflammatory gene transcription, and demyelination in the spinal cord as compared to control mice. OTUB1-deficient astrocytes were hyperactivated in response to IFN-γ, a fingerprint cytokine of encephalitogenic T cells, and produced more proinflammatory cytokines and chemokines than control astrocytes. Mechanistically, OTUB1 inhibited IFN-γ-induced Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling by K48 deubiquitination and stabilization of the JAK2 inhibitor suppressor of cytokine signaling 1 (SOCS1). Thus, astrocyte-specific OTUB1 is a critical inhibitor of neuroinflammation in CNS autoimmunity.
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Authors | Xu Wang, Floriana Mulas, Wenjing Yi, Anna Brunn, Gopala Nishanth, Sissy Just, Ari Waisman, Wolfgang Brück, Martina Deckert, Dirk Schlüter |
Journal | The EMBO journal
(EMBO J)
Vol. 38
Issue 10
(05 15 2019)
ISSN: 1460-2075 [Electronic] England |
PMID | 30944096
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2019 The Authors. |
Chemical References |
- Interferon-gamma
- Cysteine Endopeptidases
- Otub1 protein, mouse
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Topics |
- Animals
- Animals, Newborn
- Astrocytes
(immunology, metabolism, pathology)
- Autoimmunity
(genetics)
- Cells, Cultured
- Central Nervous System
(immunology, metabolism, pathology)
- Cysteine Endopeptidases
(physiology)
- Encephalomyelitis, Autoimmune, Experimental
(immunology, pathology)
- Female
- Interferon-gamma
(antagonists & inhibitors, physiology)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neurogenic Inflammation
(genetics, pathology)
- Neuroimmunomodulation
(genetics)
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