Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation

Ischemia-reperfusion (IR) injury to the renal epithelia is associated with endoplasmic reticulum stress (ERS) and mitochondria dysfunction, which lead to oxidative stress-induced acute kidney injury (AKI). X-box binding protein 1 (XBP1), an ERS response protein, could play a prominent role in IR-induced AKI. In this study, we revealed that XBP1 and its downstream target HRD1 participated in the crosstalk between ERS and mitochondrial dysfunction via regulation of NRF2/HO-1-mediated reactive oxidative stress (ROS) signaling. Mice with reduced expression of XBP1 (heterozygous Xbp1 +/-) were resistant to IR-induced AKI due to the enhanced expression of NRF2/HO-1 and diminished ROS in the kidney. Downregulation of XBP1 in renal epithelial cells resulted in reduced HRD1 expression and increased NRF2/HO-1 function, accompanied with enhanced antioxidant response. Furthermore, HRD1 served as an E3-ligase to facilitate the downregulation of NRF2 through ubiquitination-degradation pathway, and the QSLVPDI motif on NRF2 constituted an active site for its interaction with HRD1. Thus, our findings unveil an important physiological role for XBP1/HRD1 in modulating the antioxidant function of NRF2/HO-1 in the kidney under stress conditions. Molecular therapeutic approaches that target XBP1-HRD1-NRF2 pathway may represent potential effective means to treat renal IR injury.

Automated summary

This study revealed that XBP1 and its downstream target HRD1 participate in the crosstalk between ERS and mitochondrial dysfunction by regulating NRF2/HO-1-mediated ROS signaling. Downregulation of XBP1 led to reduced HRD1 expression and increased NRF2/HO-1 function, enhancing the antioxidant response in renal epithelial cells. Furthermore, HRD1 serves as an E3-ligase for NRF2 degradation, and the QSLVPDI motif on NRF2 is crucial for its interaction with HRD1.