OTUB1 non-canonically inhibits TAB2 ubiquitination to govern microglia-mediated neuroinflammation.

Microglia contribute to detrimental neuroinflammation under pathological conditions and thereby drive the pathogenesis and development of various diseases of the central nervous system (CNS). Here, the deubiquitinating enzyme OTUB1 is identified as a regulator of microglial activation and CNS inflammation. In mice, microglia-specific OTUB1 deletion significantly ameliorates ischemic brain injury by reducing the pro-inflammatory activation of microglia. OTUB1 enhances Toll-like receptor (TLR) signaling through stabilizing UBC13 and TAB2, leading to the increased induction of cytokines. Notably, OTUB1 reduces the proteasomal degradation of TAB2 by reducing its K48 ubiquitination in a catalytic activity-independent manner. Moreover, microglia-confined OTUB1 deficiency also alleviates lipopolysaccharide-induced sickness behavior and experimental autoimmune encephalomyelitis in mice due to decreased neuroinflammation. Pharmacological inhibition of OTUB1 significantly mitigated ischemic stroke injury in mice. These findings reveal an important role of OTUB1 in potentiating microglial activation and neuroinflammation, providing a proof-of-principle observation for targeting OTUB1 in the treatment of TLR-associated neuroinflammatory diseases.