Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy
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Cellular and Molecular Life Sciences
Review
Nrf2 and Nrf1 signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy Hadi Digaleh · Mahmoud Kiaei · Fariba Khodagholi
Received: 13 February 2013 / Revised: 26 May 2013 / Accepted: 13 June 2013 © Springer Basel 2013
Abstract The endoplasmic reticulum (ER) lumen is chemically complex and crowded with polypeptides in different stages of assembly. ER quality control monitors chaperone-assisted protein folding, stochastic errors and off-pathway intermediates. In acute conditions, potentially toxic polypeptides overflow the capacity of the chaperone system and lead to ER stress. Activation of the unfolded protein response (UPR) following ER stress buys time for non-native polypeptides to refold or be eliminated; otherwise cell death occurs. The clearance routes for deleterious proteins are endoplasmic reticulum-associated degradation (ERAD) and ER stress-activated autophagy. The ERAD pathway is a chaperone and proteasome-mediated polypeptide degradation, while autophagy applies to wider range of substances. ER stress signal transduction recruits diverse molecules and pathways upon UPR induction to compensate stress condition. NF-E2-related factor 1 (Nrf1) and Nrf2 are two transcription factors mostly known by their induction through an antioxidant response; they can also be activated by UPR machinery. Discovery of diverse molecules downstream of Nrf1 and Nrf2 has expanded our understanding of the biological impacts of these transcription factors beyond classic antioxidant activation. In this review, we summarize our current understanding of mutual relationships between Nrf1, Nrf2, and ER stress clearance
H. Digaleh · F. Khodagholi (*) Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran e-mail: [email protected] M. Kiaei Department of Neurobiology and Developmental Sciences, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
mechanisms and highlight the crosstalk of specific molecules mediating these correlations. Keywords Nrf1 · Nrf2 · ER stress · UPR · Autophagy · ERAD
Introduction The endoplasmic reticulum (ER) is a membranous network within the cytoplasm that is essential for the synthesis, folding, and modification of proteins destined to be secreted or embedded in the plasma membrane [1, 2]. This subcellular platform orchestrates major regulatory events in signal transduction of cellular development, differentiation, and stress. Since protein folding has a complex pathway, it is an error-prone process, resulting in unstable intermediates. Accumulation of unfolded/misfolded proteins in the lumen of ER can cause an imbalance between ER protein folding load and capacity, a condition referred to as “ER stress”, due to different physiological and pathological circumstances such as oxidative stress, glucose deprivation and excessive mutant proteins [3]. ER stress triggers an evolutionarily conserved response with an integrated signal transduction pat
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