Transcription factor NRF2 modulates chaperone mediated autophagy through the regulation of LAMP2A

Chaperone mediated autophagy (CMA) is a selective degradative pathway in which soluble proteins are translocated into lysosomes and degraded. The regulatory mechanisms that control CMA remain largely unknown but may involve response to stress conditions. Indeed, transcriptional up-regulation of LAMP2A, the limiting step for CMA, has been reported upon oxidative stress. Considering the role of CMA in redoxtasis and proteostasis, we sought to determine if the transcription factor NRF2 has an impact on CMA modulation. We first identified and validated two NRF2 binding sequences in the LAMP2 gene and demonstrated in several human and mouse cell types that NRF2 deficiency and overexpression were linked to reduced and increased LAMP2A levels, respectively. Accordingly, lysosomal LAMP2A levels were drastically reduced in Nrf2-knockout hepatocytes, which also displayed a marked decrease in CMA activity. Oxidant challenge with paraquat or hydrogen peroxide and pharmacological activation of NRF2 with sulforaphane or dimethyl fumarate increased LAMP2A levels and CMA activity. Overall, our study identifies for the first time basal and inducible regulation of LAMP2A, and consequently CMA, by the transcription factor NRF2, pointing to a new potential strategy to combat proteinopathies.