P 087 - NRF2 controls proteostasis through the transcriptional regulation of autophagy

Abstract

Cells control the abundance and quality of the proteome through a wide network that integrates signaling pathways, gene expression and protein degradation systems. Degradation of cytosolic components inside lysosomes is carried out by specific types of autophagy in mammals: macroautophagy, chaperone mediated autophagy (CMA) and microautophagy. Considering autophagy as a proteostatic and defensive mechanism, we sought to determine if this process was regulated by the transcription factor NRF2, classically considered the master regulator of the antioxidant cell response. A bioinformatics analysis allowed us to identify putative NRF2 binding sequences in macroautophagy and CMA related genes. Several were further validated as NRF2-regulated genes by ChIP assays and quantitative PCR in Nrf2-deficient cells. Consequently, Nrf2-knockout cells exhibited impaired macroautophagy flux in response to H2O2. Oxidative stress also up-regulates CMA through transcriptional induction of Lamp-2a, but to a lesser extent in Nrf2-deficient cells. Moreover, Nrf2-knockout cells showed reduced LAMP-2A lysosomal levels, the limiting step for CMA. Pharmacological activation of NRF2 led to the perinuclear accumulation of LAMP-2A positive lysosomes, indicative of CMA activation. Overall, these results point to a novel role of NRF2 in the regulation of autophagy and suggest a new strategy to combat proteinopathies.