Keap1 degradation by autophagy for the maintenance of redox homeostasis

Abstract

The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system is essential for cytoprotection against oxidative and electrophilic insults. Under unstressed conditions, Keap1 serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2, but Nrf2 is stabilized when Keap1 is inactivated under oxidative/electrophilic stress conditions. Autophagy-deficient mice show aberrant accumulation of p62, a multifunctional scaffold protein, and develop severe liver damage. The p62 accumulation disrupts the Keap1-Nrf2 association and provokes Nrf2 stabilization and accumulation. However, individual contributions of p62 and Nrf2 to the autophagy-deficiency-driven liver pathogenesis have not been clarified. To examine whether Nrf2 caused the liver injury independent of p62, we crossed liver-specific Atg7::Keap1-Alb double-mutant mice into p62-and Nrf2-null backgrounds. Although Atg7::Keap1-Alb:: p62 −/− triple-mutant mice displayed defective autophagy accompanied by the robust accumulation of Nrf2 and severe liver injury, Atg7:: Keap1-Alb::Nrf2 −/− triple-mutant mice did not show any signs of such hepatocellular damage. Importantly, in this study we noticed that Keap1 accumulated in the Atg7-or p62-deficient mouse livers and the Keap1 level did not change by a proteasome inhibitor, indicating that the Keap1 protein is constitutively degraded through the autophagy pathway. This finding is in clear contrast to the Nrf2 degradation through the proteasome pathway. We also found that treatment of cells with tert-butylhydroquinone accelerated the Keap1 degradation. These results thus indicate that Nrf2 accumulation is the dominant cause to provoke the liver damage in the autophagy-deficient mice. The autophagy pathway maintains the integrity of the Keap1-Nrf2 system for the normal liver function by governing the Keap1 turnover.electrophile | polyubiquitination

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

“…The p62-dependent autophagic degradation of Keap1 is another mechanism of Nrf2 activation and cytoprotection (Taguchi et al, 2012). This mechanism has been shown to occur in response to lipotoxicity (Park et al, 2015) or to be mediated by sestrins (Bae et al, 2013).…”

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

“…27,28 We stratified gene expression of all 211 AA genes in both LUAD and LUSC by known recurrent somatic disease-specific alterations, including EGFR and KRAS alterations, and did not find differences in core gene expression between altered and wild-type patients; however, LUSC patients with EGFR amplification had increased mRNA levels of NFE2L2 (median FC > 2; Table S5). Both overactive and impaired autophagy are hypothesized to support oncogenic NFE2L2 activity in cancer, 75 through increased degradation of the NFE2L2 sequestering protein KEAP1 51 or through reduced degradation of KEAP1 binding protein SQSTM1/p62, 76 respectively. We confirmed that both KEAP1 and NFE2L2 are significantly mutated in TCGA lung cancer patients 11 (Fig.…”

“…HNSC-G1 patients showed very poor survival and included 8/14 patients with mutated NFE2L2/NRF2 (Table S1), an important transcription factor in the oxidative stress response pathway. Activating NFE2L2 mutations have been identified in various cancers and are thought to lead to the constitutive activation of oxidative stress pathway genes that benefit tumor cell survival, 17,51 including the autophagy cargo receptor SQSTM1/p62. Overexpression of SQSTM1/p62 sets up a positive feedback loop that further activates NFE2L2 through competitive binding of the NFE2L2 inhibitor KEAP1.…”

The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells

“…This reduction was blocked by BafA1, supporting the notion that KEAP1 is degraded by selective autophagy. 60 Under resting conditions, KEAP1 sequesters NFE2L2 and targets it for proteosomal degradation. 61 Elevated cellular levels of ROS cause KEAP1 to dissociate from NFE2L2.…”