USP8 mitigates cognitive dysfunction of mice with sepsis‐associated encephalopathy

Abstract Background Sepsis‐associated encephalopathy (SAE) is a serious complication of sepsis which results from neuroinflammation and could lead to cognitive dysfunction. Ubiquitin‐specific peptidase 8 (USP8) is involved in cognitive dysfunction. This study investigated the mechanism by which USP8 plays a role in cognitive dysfunction of SAE mice. Methods The SAE models were established by performing cecal ligation and puncture in the mice. Subsequently, a series of tests and procedures were conducted to assess the cognitive dysfunction and pathological impairment of mice, including the Morris water maze test, Y‐maze test, open field test, tail suspension test, fear conditioning test, and haematoxylin–eosin staining. The levels of USP8 and Yin Yang 1 (YY1) in brain tissues of mice were detected. In order to determine the effects of USP8 or YY1 on cognitive function, SAE mice were injected with an adenovirus‐packaged vector that had overexpressed levels of USP8 or YY1 short hairpin RNA. The binding of USP8 to YY1 and the ubiquitination level of YY1 were analyzed using immunoprecipitation and ubiquitination experiments. Lastly, chromatin immunoprecipitation was carried out to analyze enrichment of YY1 on the USP8 promoter. Results In SAE models, USP8 and YY1 were downregulated and cognitive functions were impaired. USP8 overexpression upregulated YY1 and attenuated the brain histopathological damage and cognitive dysfunction in SAE mice. USP8 upregulated YY1 protein level through deubiquitination, while YY1 was enriched on the USP8 promoter and activated USP8 transcription. The effects of USP8 overexpression on SAE mice was reversed secondary to YY1 silencing. Conclusion USP8 upregulated YY1 protein level through deubiquitination and YY1 activated USP8 transcription, and USP8‐YY1 feedback loop attenuated cognitive dysfunction in SAE mice, which could potentially serve as a novel theoretical foundation for the management of SAE.