CHIP Drives Proteasomal Degradation of Nur77 to Alleviate Oxidative Stress and Intrinsic Apoptosis in Cisplatin-induced Nephropathy

Abstract

Carboxy-terminus of Hsc70-interacting protein (CHIP), an E3 ligase, modulates the stability of its targeted proteins to alleviate various pathological perturbations in various organ systems. Cisplatin is a widely used chemotherapeutic agent, but it is also known for its alarming renal toxicity. The role of CHIP in the pathogenesis of cisplatin-induced acute kidney injury (AKI) has not been adequately investigated. Herein, we demonstrate that CHIP is abundantly expressed in the renal proximal tubular epithelia, and its expression is downregulated in cisplatin-induced AKI. Further investigation revealed that CHIP overexpression or activation alleviated, while its gene disruption promoted, oxidative stress and apoptosis in renal proximal tubular epithelia induced by cisplatin. In terms of mechanism, CHIP interacted with and ubiquitinated Nur77 to promote its degradation, which consequently shielded Bcl2 to maintain mitochondrial permeability of renal proximal tubular cells in the presence of cisplatin. Also, we demonstrate that CHIP interacts with Nur77 via its central coiled-coil (CC) domain, a non-canonical interactive pattern. In conclusion, these findings indicate that CHIP ubiquitinates and degrades its substrate Nur77 to attenuate intrinsic apoptosis in cisplatin-treated renal proximal tubular epithelia, thus providing a novel insight for the pathogenesis of cisplatin-induced AKI.