Unraveling the NRF2 confusion: Distinguishing nuclear respiratory factor 2 from nuclear erythroid factor 2

Abstract

In recent years, the acronym NRF2 has garnered significant attention in scientific discourse. However, this attention has occasionally led to confusion due to the existence of two distinct proteins sharing the same acronym: Nuclear Respiratory Factor 2 (NRF2), also known as GA-binding protein transcription factor subunit alpha (GABPA), and Nuclear Factor Erythroid 2-related Factor 2 (NFE2L2 or NRF2). This confusion has been highlighted in various scientific forums, including PubPeer and anonymous reader comments, where the confusion between the two proteins has been expressed. In this article, we aim to elucidate the disparities between these two proteins. Both are transcription factors that play pivotal roles in cellular homeostasis and response to stress, with some overlapping functional aspects. Nuclear Factor Erythroid 2-related Factor 2 (NFE2L2) is a key regulator of the antioxidant response element (ARE) pathway. It functions by binding to antioxidant response elements in the promoters of target genes, thereby orchestrating the expression of various cytoprotective enzymes and proteins involved in detoxification, redox balance, and cellular defense against oxidative stress. Conversely, Nuclear Respiratory Factor 2 (GABPA) is primarily associated with the regulation of mitochondrial biogenesis, in relation to PGC1α, and maintaining cellular energy metabolism. It is important to recognize and differentiate between these two proteins to avoid misconceptions and misinterpretations in scientific literature and discussions. Our laboratories (Arubala P Reddy and P. Hemachandra Reddy) focued on Nuclear Respiratory Factor 2 (NRF2), but not on Nuclear Factor Erythroid 2-related Factor 2 (NFE2L2). We hope that the facts, figures, and discussions presented in this article will clarify the current controversy regarding the sizes, structural features, and functional aspects of these proteins.

Keywords: 2GA-binding protein transcription factor subunit alpha; Mitochondria; Nuclear erythroid factor 2; Nuclear factor erythroid 2-related factor; Nuclear respiratory factor; Oxidative stress.

Figure 1-

PGC-1α takes the reins in regulating mitochondrial biogenesis by activating NRF1 and NRF2. This tag team effort boosts the expression of TFAM, a key player in mitochondrial DNA transcription and replication, ensuring a robust energy production system within the cell.

Figure 2:

Mitochondrial Biogenesis – a mechanistic pathway of how cells initiate mitochondrial reproduction. Activators: MAPK and AMPK positively phosphorylate PGC1α, SIRT1 deacetylates PGC1α, PRMT methylates PGC1α, and BAP1/OGT complex removes ubiquitin from PGC1α. NFAT, MEF2, and CREB are transcription factors that positively regulate PGC1α. Activation of the PGC1α pathway will increase protein transcription of PPARs, ERRs, NRFs, and TFAM.

Figure 3:

Illustrated in the schematic is the journey of NFE2L2 or NFEF2-ARE as it relocates from the cytoplasm to the nucleus post-release from its suppressor, Keap1. Within the nucleus, NRF2 interfaces with antioxidant response elements (AREs) on DNA strands, instigating the activation of numerous genes pivotal in managing oxidative stress reactions. Noteworthy players in this process include Keap1 (Kelch-like ECH-associated protein-1) as the inhibitor, and NRF2 (nuclear factor erythroid-2-related factor 2) as the pivotal regulator.