OTUB1 inhibits CNS autoimmunity by preventing IFN‐γ‐induced hyperactivation of astrocytes. (3rd April 2019)

• Record Type: Journal Article
• Authors: Wang, Xu; Mulas, Floriana; Yi, Wenjing; Brunn, Anna; Nishanth, Gopala; Just, Sissy; Waisman, Ari; Brück, Wolfgang; Deckert, Martina; Schlüter, Dirk
• Is Part Of: EMBO journal. Volume 38:Number 10(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-04-03
• Subjects: astrocyte -- experimental autoimmune encephalomyelitis -- multiple sclerosis -- neuroinflammation -- OTUB1 -- ubiquitination; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2018100947
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: The deubiquitinating enzyme OTUB1 regulates cell signaling by blocking ubiquitin transfer from E2 conjugating enzymes to E3 ligases or by cleavage of ubiquitin chains from target proteins, but the in vivo cell type‐specific function of OTUB1 is largely unknown. During CNS autoimmunity, human and murine astrocytes upregulate OTUB1, which limits CNS pathology by inhibiting IFN‐γ‐induced activation of the JAK2/STAT1 pathway and concomitant chemokine and cytokine production in astrocytes. OTUB1 expression of astrocytes is induced in the CNS of treatment‐naïve patients with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. OTUB1 inhibits IFN‐γ‐induced JAK2/STAT1 signaling by K48 deubiquitination and stabilization of the JAK2 inhibitor SOCS1. OTUB1‐dependent inhibition of the JAK2/STAT1 signaling limits IFN‐γ‐induced cytokine and chemokine production of astrocytes. OTUB1 expression in astrocytes ameliorates the clinical severity of murine experimental autoimmune encephalomyelitis by limiting astrocytic cytokine and chemokine production, recruitment of encephalitogenic T cells to the CNS, and demyelination. Abstract : Upregulation of the OTUB1 deubiquitinase in nervous system autoimmune conditions such as multiple sclerosis stabilizes the JAK/STAT inhibitor SOCS1 to reduce astrocyte‐mediated neuroinflammatory responses.