Role of the OTUB1/IRF7/NOX4 axis in oxidative stress injury and inflammatory responses in mice with Parkinson's disease

Abstract

Background: Parkinson's disease (PD) is one of the most devastating neurodegenerative disorders and is associated with oxidative stress injury (OSI) and inflammatory responses. This study sought to investigate the mechanism of ovarian tumour domain-containing ubiquitin aldehyde binding 1 (OTUB1) in OSI and inflammatory responses in PD, providing a theoretical foundation for PD treatment. Methods: The PD mouse model was established by an intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, followed by behavioural tests, observation of brain pathological changes, and quantification of inflammatory (TNF-α, IL-1β, and IL-10) and OS (ROS, SOD, and MDA) factors. Next, the expression levels of OTUB1, interferon regulatory factor 7 (IRF7), and NADPH oxidase 4 (NOX4) levels were determined by real-time quantitative polymerase chain reaction and western blot assay, the binding of OTUB1 to IRF7 was analysed by co-immunoprecipitation, and the ubiquitination level of IRF7 and the enrichment and binding of IRF7 and the NOX4 promoter were measured by chromatin immunoprecipitation and dual-luciferase assays. Afterwards, rescue experiments were performed with IRF7 or NOX4 overexpression in OTUB1 knockout PD mice. Results: OTUB1 was upregulated in brain tissues of PD mice. Inhibition of OTUB1 alleviated PD progression, OSI, and inflammatory responses. OTUB1 stabilized IRF7 through deubiquitination, and IRF7 bound to the NOX4 promoter to promote NOX4 expression. IRF7 or NOX4 overexpression reversed the effects of silencing OTUB1 on OSI and inflammatory responses in PD mice. Conclusion: OTUB1-mediated deubiquitination stabilized IRF7 and upregulated NOX4 expression, thereby promoting OSI and inflammatory responses in PD mice.

OTUB1-mediated inhibition of ubiquitination: a growing list of effectors, multiplex mechanisms, and versatile functions

“…In addition, there are other proteins reported to be regulated by OTUB1, albeit the exact mechanisms require further delineation. These proteins include TRAF3 ( Li et al, 2010 ; Peng et al, 2014 ; Xie et al, 2020 ), TRAF6 ( Li et al, 2010 ; Zhang et al, 2022 ), YB-1 ( Dong et al, 2015 ), RPA1 ( Wang et al, 2015 ), Cyclin E1 ( Liao et al, 2020 ), ATF6 ( Zhang et al, 2021a ), E2F1 ( Zhang et al, 2021b ), IAP-1 ( Koschel et al, 2021 ), EYA1 ( Xie et al, 2021 ), HSF1 ( Ling et al, 2022 ), IRF7 ( Xing et al, 2023 ), TAZ ( Nakagawa et al, 2023 ), and RACK1 ( Li et al, 2023b ).…”