YOD1 drives acute kidney injury by deubiquitinating Bax and promoting apoptosis in tubular epithelial cells.

RATIONALE: Acute kidney injury (AKI) is a life-threatening clinical syndrome characterized by high mortality, in which tubular epithelial cell death represents a key pathological event. Emerging evidence underscores the importance of the ubiquitin system in the progression of AKI. Here, we focus on the function of YOD1 in AKI.

METHODS

We generated tubular epithelial cells (TECs)-specific Yod1 knockout mice (YOD1CKO) by crossing Yod1fl/fl mice and Ggt1-cre mice. Both YOD1CKO mice and Yod1fl/fl littermates were subjected to cisplatin- or ischemia/reperfusion (I/R)-induced AKI models. Through co-immunoprecipitation (Co-IP) combined with LC-MS/MS analysis, we identified potential substrate proteins of YOD1.

RESULTS

We observed that YOD1 is predominantly expressed in TECs and is upregulated during AKI injury. Renal tubular specific Yod1 knockout significantly alleviated tubular damage and apoptosis in AKI mice. Mechanistically, we identified the pro-apoptotic protein Bax as a direct substrate of YOD1. YOD1 removes K63-linked ubiquitin chains from Bax at lysine 128 via its catalytic cysteine residue C155, thereby promoting Bax activation, and mitochondrial translocation and subsequent apoptosis. YOD1 failed to promote apoptosis in Bax-deficient cells, confirming Bax as the essential downstream mediator.

CONCLUSIONS

Our study reveals a previously unrecognized YOD1-Bax regulatory axis that drives tubular apoptosis in AKI, and highlights YOD1 may hold therapeutic potential.