Chaperone-mediated autophagy degrades Keap1 and promotes Nrf2-mediated antioxidative response

Accumulation of oxidative stress is highly intertwined with aging process and contributes to aging-related diseases, such as neurodegenerative diseases. Deciphering the molecular machinery that regulates oxidative stress is fundamental to further uncovering the pathogenesis of these diseases. Chaperone-mediated autophagy (CMA), a highly selective lysosome-dependent degradation process, has been proven to be an important maintainer of cellular homeostasis through multiple mechanisms, one of which is the attenuation of oxidative stress. However, the specific mechanisms underlying this antioxidative action of CMA are not fully understood. In this study, we found that CMA directly degrades Kelch-like ECH-associated protein 1 (Keap1), an adaptor of E3 ligase complex that promotes the degradation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is a master transcriptional regulator in antioxidative response. Activated CMA induced by prolonged oxidative stress led to an increase in Nrf2 level by effectively degrading Keap1, contributing to Nrf2 nuclear translocation and the expression of multiple downstream antioxidative genes. Meanwhile, together with previous study showing that Nrf2 can also transcriptionally regulate LAMP2A, the rate-limiting factor of CMA process, we reveal a feed-forward loop between CMA and Nrf2. Our study identifies CMA as a previously unrecognized regulator of Keap1-Nrf2 pathway and reinforces the antioxidative role of CMA.

Automated summary

Accumulation of oxidative stress is closely associated with aging and aging-related diseases. Understanding the molecular mechanisms that regulate oxidative stress is crucial for uncovering the pathogenesis of these diseases. Chaperone-mediated autophagy (CMA), a selective lysosome-dependent degradation process, has been shown to maintain cellular homeostasis and attenuate oxidative stress. This study reveals that CMA directly degrades Keap1, leading to increased Nrf2 levels, nuclear translocation, and expression of antioxidative genes. Furthermore, a feed-forward loop between CMA and Nrf2 is identified. These findings highlight the role of CMA as a regulator of the Keap1-Nrf2 pathway and emphasize its antioxidative function.