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OTUB1 inhibits CNS autoimmunity by preventing IFN-?-induced hyperactivation of astrocytes

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

SUBMITTER: Dr. Xu Wang

PROVIDER: S-SCDT-EMBOJ-2018-100947 | biostudies-other |

REPOSITORIES: biostudies-other

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