Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation.
Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation.
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XBP1 下调通过抑制 HRD1 介导的 NRF2 泛素化保护肾脏免受缺血再灌注损伤
DOI：
10.1038/s41420-021-00425-z
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发表时间：
2021-03-02
影响因子：
7
通讯作者：
Gong N
中科院分区：
文献类型：
--
作者：
Zhang J;Zhang J;Ni H;Wang Y;Katwal G;Zhao Y;Sun K;Wang M;Li Q;Chen G;Miao Y;Gong N
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.
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影响因子：
64.5
作者：
Cubillos-Ruiz JR;Silberman PC;Rutkowski MR;Chopra S;Perales-Puchalt A;Song M;Zhang S;Bettigole SE;Gupta D;Holcomb K;Ellenson LH;Caputo T;Lee AH;Conejo-Garcia JR;Glimcher LH
通讯作者：
Glimcher LH
影响因子：
7.5
作者：
Wang S;Gumpper K;Tan T;Luo X;Guo H;Ming C;Jiang H;Fang J;Du G;Zhu H;Ma J;Chen Z;Gong N
通讯作者：
Gong N
影响因子：
64.8
作者：
Chen, Xi;Iliopoulos, Dimitrios;Zhang, Qing;Tang, Qianzi;Greenblatt, Matthew B.;Hatziapostolou, Maria;Lim, Elgene;Tam, Wai Leong;Ni, Min;Chen, Yiwen;Mai, Junhua;Shen, Haifa;Hu, Dorothy Z.;Adoro, Stanley;Hu, Bella;Song, Minkyung;Tan, Chen;Landis, Melissa D.;Ferrari, Mauro;Shin, Sandra J.;Brown, Myles;Chang, Jenny C.;Liu, X. Shirley;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
影响因子：
8
作者：
Chowdhry, S.;Zhang, Y.;McMahon, M.;Sutherland, C.;Cuadrado, A.;Hayes, J. D.
通讯作者：
Hayes, J. D.
影响因子：
10.5
作者：
Amano, T;Yamasaki, S;Nakajima, T
通讯作者：
Nakajima, T