JOSD2 alleviates acute kidney injury through deubiquitinating SIRT7 and negativity regulating SIRT7-NF-κB inflammatory pathway in renal tubular epithelial cells.

Abstract

Acute kidney injury (AKI), triggered by various stimuli including ischemia-reperfusion, nephrotoxic insult, and sepsis, is characterized by an abrupt deterioration in kidney function. Ubiquitination is a post-translational modification of proteins that plays a critical role in the pathogenesis and progression of AKI. In this study, we aimed to investigate the role and underlying mechanism of the deubiquitinating enzyme Josephin Domain-containing protein 2 (JOSD2) in AKI. We found that deficiency of JOSD2 exacerbated renal tubular injury and inflammation in AKI mice induced by cisplatin or ischemia-reperfusion injury. Conversely, the specific overexpression of JOSD2 in renal tubular epithelial cells effectively prevented renal tubular injury and inflammation induced in AKI mice. Mechanistically, we identified Sirtuin 7 (SIRT7) as a potential substrate of JOSD2 through mass spectrometry combined with co-immunoprecipitation analysis. JOSD2 removes the K63-linked ubiquitination of SIRT7 via its active site C24 and promotes P62-mediated autophagic degradation of SIRT7, which subsequently prevents the phosphorylation and nuclear translocation of P65 and reduces inflammatory responses in renal tubular epithelial cells. Our study reveals the role of the JOSD2-SIRT7 axis in regulating AKI-induced renal inflammation and highlights the potential of JOSD2 as a promising therapeutic target for AKI.