Universität zu Köln

Wang, Xu, Mulas, Floriana, Yi, Wenjing, Brunn, Anna, Nishanth, Gopala, Just, Sissy, Waisman, Ari ORCID: 0000-0003-4304-8234, Bruecks, Wolfgang, Deckert, Martina and Schlueter, Dirk (2019). OTUB1 inhibits CNS autoimmunity by preventing IFN-gamma-induced hyperactivation of astrocytes. Embo J., 38 (10). HOBOKEN: WILEY. ISSN 1460-2075

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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-gamma, a fingerprint cytokine of encephalitogenic T cells, and produced more proinflammatory cytokines and chemokines than control astrocytes. Mechanistically, OTUB1 inhibited IFN-gamma-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wang, Xu UNSPECIFIED UNSPECIFIED UNSPECIFIED Mulas, Floriana UNSPECIFIED UNSPECIFIED UNSPECIFIED Yi, Wenjing UNSPECIFIED UNSPECIFIED UNSPECIFIED Brunn, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Nishanth, Gopala UNSPECIFIED UNSPECIFIED UNSPECIFIED Just, Sissy UNSPECIFIED UNSPECIFIED UNSPECIFIED Waisman, Ari UNSPECIFIED orcid.org/0000-0003-4304-8234 UNSPECIFIED Bruecks, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Deckert, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlueter, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-148172
DOI:	10.15252/embj.2018100947
Journal or Publication Title:	Embo J.
Volume:	38
Number:	10
Date:	2019
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1460-2075
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; MULTIPLE-SCLEROSIS; GENE-EXPRESSION; INTERFERON-BETA; ENCEPHALOMYELITIS; SPECIFICITY; BINDING; PROTEIN; DEUBIQUITINATION; TRANSCRIPTION Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14817