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OTUB1 Inhibits CNS Autoimmunity by Preventing IFN-γ-induced Hyperactivation of Astrocytes

OTUB1 Inhibits CNS Autoimmunity by Preventing IFN-γ-induced Hyperactivation of Astrocytes

Xu Wang, Floriana Mulas, Wenjing Yi, Anna Brunn, Gopala Nishanth, Sissy Just, Ari Waisman, Wolfgang Brück, Martina Deckert, Dirk Schlüter

EMBO J. 2019 May 15;38(10):e100947.

PMID: 30944096

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42410922	Ubiquitin Aldehyde			Price

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