OTUB1 inhibits CNS autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes.
Animals
Animals, Newborn
Astrocytes
/ immunology
Autoimmunity
/ genetics
Cells, Cultured
Central Nervous System
/ immunology
Cysteine Endopeptidases
/ physiology
Encephalomyelitis, Autoimmune, Experimental
/ immunology
Female
Interferon-gamma
/ antagonists & inhibitors
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurogenic Inflammation
/ genetics
Neuroimmunomodulation
/ genetics
OTUB1
astrocyte
experimental autoimmune encephalomyelitis
multiple sclerosis
neuroinflammation
ubiquitination
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
15 05 2019
15 05 2019
Historique:
received:
17
10
2018
revised:
20
02
2019
accepted:
28
02
2019
pubmed:
5
4
2019
medline:
7
1
2020
entrez:
5
4
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30944096
pii: embj.2018100947
doi: 10.15252/embj.2018100947
pmc: PMC6517825
pii:
doi:
Substances chimiques
Interferon-gamma
82115-62-6
Cysteine Endopeptidases
EC 3.4.22.-
Otub1 protein, mouse
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2019 The Authors.
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