OTUD1 positively regulates microglia neuroinflammation and promotes the pathogenesis of Alzheimer's disease by deubiquitinating C/EBPβ.

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Microglia-mediated neuroinflammation is closely associated with AD pathogenesis. Abnormal deubiquitinating enzyme (DUB) expression is associated with neuroinflammation. Identification of functional DUBs in microglia may provide novel targets for AD treatment. Here, we found that the levels of DUB, ovarian tumor deubiquitinase 1 (OTUD1), were upregulated in AD model mice and amyloid-beta-induced microglia. OTUD1 knockdown in microglia significantly inhibited neuroinflammation, thereby improving cognitive impairment in AD model mice. Liquid chromatography-tandem mass spectrometry analysis coupled with co-immunoprecipitation revealed the CCAAT/enhancer-binding protein β (C/EBPβ), a key transcription factor regulating microglial inflammation, as an OTUD1-interacting protein. Mechanistically, OTUD1 bound to C/EBPβ and maintained its stability by removing the K48 ubiquitin chain at K253 of C/EBPβ, thereby activating the C/EBPβ-nuclear factor-κB-mediated inflammatory responses in microglia. Overall, our results revealed the roles of the OTUD1-C/EBPβ axis in mediating the microglial inflammatory responses and AD pathology, facilitating the development of new strategies targeting microglial neuroinflammation for AD treatment.