Unravelling the role of NFE2L1 in stress responses and related diseases

Abstract

The nuclear factor erythroid 2 (NF-E2)-related factor 1 (NFE2L1, also known as Nrf1) is a highly conserved transcription factor that belongs to the CNC-bZIP subfamily. Its significance lies in its control over redox balance, proteasome activity, and organ integrity. Stress responses encompass a series of compensatory adaptations utilized by cells and organisms to cope with extracellular or intracellular stress initiated by stressful stimuli. Recently, extensive evidence has demonstrated that NFE2L1 plays a crucial role in cellular stress adaptation by 1) responding to oxidative stress through the induction of antioxidative responses, and 2) addressing proteotoxic stress or endoplasmic reticulum (ER) stress by regulating the ubiquitin-proteasome system (UPS), unfolded protein response (UPR), and ER-associated degradation (ERAD). It is worth noting that NFE2L1 serves as a core factor in proteotoxic stress adaptation, which has been extensively studied in cancer and neurodegeneration associated with enhanced proteasomal stress. In these contexts, utilization of NFE2L1 inhibitors to attenuate proteasome "bounce-back" response holds tremendous potential for enhancing the efficacy of proteasome inhibitors. Additionally, abnormal stress adaptations of NFE2L1 and disturbances in redox and protein homeostasis contribute to the pathophysiological complications of cardiovascular diseases, inflammatory diseases, and autoimmune diseases. Therefore, a comprehensive exploration of the molecular basis of NFE2L1 and NFE2L1-mediated diseases related to stress responses would not only facilitate the identification of novel diagnostic and prognostic indicators but also enable the identification of specific therapeutic targets for NFE2L1-related diseases.

Keywords: Adaptive responses; Cancer; NFE2L1; Neurodegeneration; Oxidative stress; Proteasome.

Graphical abstract

Fig. 1

The structure of NFE2L1. A. Structural prediction was downloaded from the Alphafold project (https://alphafold.com/entry/A0A384A8U2) [33,34]. B. Functional domains of NFE2L1 in mouse (the top) and its homologus SKN-1A in C. elegans (the bottom) are illustrated. The sites subject to selective proteolysis or N-glycosylation are labelled. The sequences refer to the National Center for Biotechnology (NCBI) (www.ncbi.nlm.nih.gov). NTD = N-terminal domain, TM = transmembrane domain, AD = acidic domain, CRAC = cholesterol-recognition/amino acid consensus motif, NST = N-X-S/T-rich domain, SR = serine-repeat, Neh6L = Nrf2–ECH homology 6-like, CNC = Cap ‘n’ collar, bZIP = basic-region zipper, BR = basic region.

Fig. 2

NFE2L1-mediated resistance to ferroptosis. GSH biosynthesis is critical for protecting cells from oxidative damage and ferroptosis, the biogenesis of which is catalysed by a series of enzymes regulated by NFE2L1. NFE2L1 also induces the expression of ROS scavengers, such as SOD and PRDX, to inhibits lipid peroxidation. Besides, NFE2L1 can promote ferroptosis resistance by maintaining the protein level of GPX4 in a transcription-independent way. Moreover, the ability of NFE2L1 to maintain normal proteosome activity and proteostasis has been attached great importance in mediating resistance to ferroptosis, although the detailed mechanism remains unclarified. ox-LDL = oxidized-low density lipoprotein, CoA = coenzyme A, PUFA = polyunsaturated fatty acid, PL-PUFA = polyunsaturated phospholipid, PL-OOH = phospholipid hydroperoxide, ECT = electron transport chain, OXPHOS = oxidative phosphorylation, ROS = reactive oxygen species, SOD = superoxide dismutases, PRDX = peroxiredoxins, GCL = glutamate-cysteine ligase, GSS = glutathione synthetase, GSH = glutathione, GPX4 = glutathione peroxidase 4, ACSL4 = acyl-CoA synthetase long-chain family member 4, LPCAT3 = lysophosphatidylcholine acyltransferase 3, LOX = lipoxygenase, POR = cytochrome p450 oxidoreductase, TfR1 = transferrin receptor 1, DMT1 = divalent metal transporter 1, STEAP3 = six-transmembrane epithelial antigen of prostate 3.

Fig. 3

NFE2L1 is postulated to be cooperated with UPR^ER. UPR activation is achieved by three ER stress sensors (i.e., PERK, IRE1α, and ATF6) with the corresponding representative signalling pathways as illustrated above. (1) NFE2L1 can be activated via PERK/elF2α/ATF4 axis. In addition, NFE2L2 can also be activated by dimerized PERK to maintain redox homeostasis. (2) IRE1α can be dimerized under ER stress to enable XBP1s to transactivate ATF4/5, BiP and HSP4, thus it is proposed that XBP1s can indirectly activate NFE2L1 to further promote the ER expansion, ERAD and lipid metabolism. (3) Activated ATF6 may lead to NFE2L1 induction indirectly via ATF6/XBP1/ATF4 pathway. (4) JNK is speculated to phosphorylate and activate NFE2L1. PI3K/Akt signalling and RAS/MAPK signalling also participate in NFE2L1 activation via (5) mTORC1/SREBP1/NFE2L1 pathway or (6) mTORC1/STAT3/NFE2L1 pathway. NFE2L1/2 = nuclear factor erythroid 2 (NF-E2)-related factor 1/2, ERAD = ER-associated degradation, PERK = UPR mediator pancreatic ER kinase (PKR)-like ER kinase, GCN2 = general control nonderepressible 2, eIF2α = eukaryotic translation initiation factor 2 subunit alpha, ATF4/5/6 = activating transcription factor 4/5/6, CHOP = C/EBP-Homologous Protein, C/EBPα = CCAAT enhancer binding protein alpha, KEAP1 = Kelch like ECH associated protein 1, S1P/S2P = Golgi-resident site-1/2 protease, SREBP1 = sterol regulatory element-binding protein 1, PI3K = phosphatidylinositol 3-kinase, TSC1/2 = tuberous sclerosis complex 1/2, mTORC1 = mechanistic target of rapamycin complex 1, STAT3 = signal transducer and activator of transcription 3, RSK = Ribosomal S6 kinase, AMPK = AMP-activated protein kinase, IRE1α = inositol-requiring enzyme 1alpha, JNK = c-jun N-terminal kinase, XBP1s = spliced x-box-binding protein 1, RIDD = IRE1alpha-dependent decay, ERSE = endoplasmic reticulum stress response elements, SRE = serum response elements, UPRE = unfolded protein response elements, BiP = Binding immunoglobulin protein.