Fig. 3

DUBs regulate EAE by modulating signal transduction in astrocytes and microglia. In addition to immune cells, the onset and perpetuation of EAE can also be influenced by astrocytes and microglia, two CNS-resident cell populations with immune-regulating properties. Production of type I IFNs is induced by RIG-1-initiated signaling, and the activity of RIG-1 is enhanced by TRIM25, which mediates K63 ubiquitination of RIG-1. By deubiquitinating and stabilizing TRIM25, USP15 enhances RIG-1-dependent type I IFN production. Microglia activation induced by type I IFNs is detrimental for EAE, but it can be inhibited by USP18, which directly interacts with IFNAR2 and inhibits downstream signaling. IFN-γ, the type II IFN, induces the production of multiple cytokines and chemokines in astrocytes. IFN-γ-induced astrocyte activation is inhibited by OTUB1, which K48 deubiquitinates and stabilizes SOCS1, an inhibitor of JAK2. In addition to OTUB1, IFN-γ-induced astrocyte activation can also be inhibited by A20, which inhibits STAT1 transcription. A20 is a versatile ubiquitin-modifying enzyme and it processes both DUB and E3 ligase activities. Upon TNF stimulation, A20 catalyzes K48 ubiquitination of RIPK1 after removing K63 ubiquitin chains from it. Apart from RIPK1, activity of IKKγ is also inhibited by A20, which reduces M1 and K63 ubiquitination of IKKγ