TRIM21 ubiquitylates GPX4 and promotes ferroptosis to aggravate ischemia/reperfusion-induced acute kidney injury
- Life Sci. 2023 Mar 21;121608. doi: 10.1016/j.lfs.2023.121608.
- 1. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
- 2. Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.
- 3. Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
- 4. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: [email protected].
Aims: This study aims to verify the molecular mechanism that Tripartite motif containing 21 (TRIM21) promotes ubiquitination degradation of Glutathione Peroxidase 4 (GPX4) by regulating Ferroptosis, and to discuss the feasibility of TRIM21 as a new therapeutic target for acute kidney injury (AKI).
Materials and methods: Ischemia-reperfusion (I/R)-AKI model was constructed using TRIM21+/+ and TRIM21-/- mice, and the expression of markers associated with kidney injury and Ferroptosis were evaluated. HK-2 cells were treated by RSL3 and Erastin, and a hypoxia/reoxygenation (H/R) model was constructed to simulate I/R injury in vivo.
Key findings: In vivo, TRIM21 is highly expressed in I/R kidney tissues. Loss of TRIM21 alleviated I/R-AKI and improved renal function. The upregulation of GPX4, a key Ferroptosis regulator, and the mild mitochondrial damage suggested that loss of TRIM21 had a negative regulation of Ferroptosis. In vitro, TRIM21 was highly expressed in H/R models, and overexpression of TRIM21 in HK-2 cells increased ROS production, promoted intracellular iron accumulation, and boosted cellular sensitivity to RSL3 and Erastin. Mechanistically, we confirmed that GPX4 is a substrate of TRIM21 and can be degraded by TRIM21-mediated ubiquitination, suggesting that inhibiting TRIM21 attenuates Ferroptosis. A JAK2 Inhibitor Fedratinib downregulated TRIM21 expression and reduced damage both in vivo and in vitro, which is correlated with the upregulation of GPX4.
Significance: Our study showed that loss of TRIM21 could alleviate Ferroptosis induced by I/R, revealed the mechanism of ubiquitination degradation of GPX4 by TRIM21 and suggested TRIM21 is a potential target for the treatment of AKI.