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FLASH GENE
Symbol NFE2L2 contributors: mct/npt/pgu/shn - updated : 02-07-2016
HGNC name nuclear factor (erythroid-derived 2)-like 2
HGNC id 7782
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N terminal acid activation domain
  • basic leucine zipper (bZIP) protein
  • two transcription activation domains Neh4 and Neh5
  • a transactivation carboxy-terminal Neh3 domain
  • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies ortholog to Nfe2l2, Mus musculus
    ortholog to Nfe2l2, Rattus norvegicus
    ortholog to NFE2L2, pan troglodytes
    Homologene
    FAMILY
  • Cap'n'collar (CNC) family of transcription factor
  • bZIP family
  • CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    text
  • sequestered in the cytoplasm by the actin-binding protein KEAP1
  • predominantly in the cytoplasm where it interacts with KEAP1 (
  • PALB2 regulates the rate of NFE2L2 export from the nucleus following induction
  • stimuli that activate the NFE2L2 pathway [oxidative stress, kinase activation, or treatment by small molecules, such as sulforaphane (SLF)] lead to NFE2L2 translocation into the nucleus
  • basic FUNCTION
  • regulating expression of genes encoding enzymes with antioxidant
  • master regulator of response to oxidative stress
  • playing a protective role against acetaminophen hepatotoxicity by regulating drug metabolizing and antioxidant enzyme genes through the ARE (antioxidant responsive element)
  • role in detoxification of acetaminophen
  • a critical effector of PERK-mediated cell survival
  • a pivotal role of Nrf2-antioxidant responsive element pathway in the cellular antioxidant defense system
  • PI3K and ERK/Nrf2 signaling pathway controls the intracellular levels of ROS by regulating the expression of the antioxidant enzyme HO-1
  • regulate a battery of antioxidant and xenobiotic-metabolizing enzyme genes through the antioxidant response element (ARE)
  • principal regulator of ARE-mediated transactivation
  • regulates expression of AHR and subsequently modulates several downstream events of the AHR signaling cascade, including transcriptional control of the xenobiotic metabolism genes CYP1A1 and CYP1B1
  • directly modulates AHR signaling, highlighting bidirectional interactions of these pathways
  • regulates oxidized LDL-mediated CD36 expression in macrophages
  • directly regulates CD36 gene expression by binding to 1A-antioxidant response elements 2
  • activating the production, recycling and release of glutathione and cysteine by suprabasal keratinocytes resulting in protection of basal cells
  • key regulator in the UV response of the skin
  • induces the expression of antioxidant gene products that neutralize reactive oxygen species and restore redox homeostasis
  • basic leucine zipper transcription factor that regulates the expression of cytoprotective and detoxifying genes
  • NFE2L2 is one of the major factors involved in the AKR1B10 gene regulation
  • plays a crucial role in cellular defence against oxidative stress by inducing the expression of multiple anti-oxidant genes
  • has an essential protective role in the lungs through the activation of antioxidant response element-regulated antioxidant and cytoprotective genes
  • its antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis
  • role for the KEAP1-NFE2L2 pathway in mediating chemotherapeutic responses in the epithelial ovarian cancer
  • role of NFE2L2 in control of BCL2 expression and apoptotic cell death with implications in antioxidant protection, survival of cancer cells, and drug resistance
  • NFE2L2-mediated up-regulation of BCL2 plays a significant role in prevention of apoptosis, increased cell survival, and drug resistance
  • NFE2L2-mediated reduced apoptotic cell death plays a significant role in the survival of oncogenic cells and drug resistance
  • KLF2 and NFE2L2 are major transcriptional factors that contribute to anti-atherogenic responses under laminar flow
  • transcriptional master regulator of the stress-induced antioxidant response
  • is a major transcriptional activator of cytoprotective genes against oxidative/electrophilic stress
  • participation of NFE2L2 in a WNT regulated signalosome that participates in basal maintenance of hepatic antioxidant metabolism
  • NFE2L2 induction in skeletal muscle (SkM) increases GBE1 and PHKA1 expression and reduces muscle glycogen content, resulting in improved glucose tolerance
  • NFE2L2 is a regulator of autophagy gene expression
  • age-dependent declines in NFE2L2 expression impact likely mitochondrial motility and induce functional deficits commonly linked to neurodegeneration
  • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS immunity/defense
    text
  • a key cellular sensor of oxidative stress
  • PATHWAY
    metabolism
    signaling
  • autophagy pathway maintains the integrity of the KEAP1-NFE2L2 system for the normal liver function by governing the KEAP1 turnover
  • importance of the NFE2L2-GPX7 pathway in pro-longevity signaling
  • laminar flow-induced activation of MAPK7-NFE2L2 signal pathway plays a critical role for anti-inflammatory and anti-apoptotic mechanism in endothelial cells
  • a component
  • heterodimer NFE2L2/ATF4
  • heterodimer with a small MAF protein and binds to its cognate DNA sequence
  • NFE2L2 serves as a substrate adaptor to link NFE2L2 to CUL3 and RBX1 (NFE2L2 regulates CUL3-RBX1 by controlling regulation of expression and induction of CUL3-RBX1, and the induction of CUL3-RBX1 control NFE2Lf2 by increasing degradation)
  • CBR3 is a new member of the NFE2L2 gene battery
  • SQSTM1-NFE2L2-NQO1 cascade functions to assure mammalian longevity by stabilizing mitochondrial integrity
  • KEAP1-NFE2L2 system and autophagy are both involved in the oxidative-stress response, metabolic pathways, and innate immunity, and dysregulation of these processes is associated with pathogenic processes
  • KEAP1-NFE2L2 system regulates the cell fate determination of hematopoietic stem cells
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • c-Jun, Jun-B and Jun-D
  • antioxidant response element, ARE and v-maf musculoaponeurotic fibrosarcoma oncogene homolog K (avian), MAFK
  • regulates both baseline and inducible expression of a battery of antioxidant and phase II detoxification enzymes
  • peroxisome proliferator-activated receptor gamma, PPARgamma
  • polyamine modulated factor-1, PMF-1
  • activating transcription factor 4, ATF4
  • CREB (cAMP Responsive Element Binding protein) Binding Protein, CBP
  • Polyamine-modulated factor 1, PMF-1 and COP9 signalosome subunit 7a, CSN 7
  • MafF
  • kelch-like ECH-associated protein 1, KEAP1
  • Glucocorticoid receptor, GR
  • chromodomain helicase DNA binding protein 6, CDH6
  • transcription activator BRG1
  • p21(Cip1/WAF1)
  • c-Myc
  • CR6-interacting factor 1, CRIF1
  • HDAC2
  • TRIM28
  • KRAS and MYC
  • AMER1 and NFE2L2 compete for binding to KEAP1, and thus loss of AMER1 leads to rapid ubiquitination and degradation of NFE2L2 and a reduced response to cytotoxic insult
  • PALB2 regulates the rate of NFE2L2 export from the nucleus following induction
  • CBR3 is a target gene of NFE2L2, a cellular sensor of oxidative stress
  • antioxidant function of PARK7 by increasing TXN expression via NFE2L2-mediated transcriptional induction
  • is an important factor in upregulating TXN expression under stress conditions
  • BTG2 is a binding partner for NFE2L2 and increases its transcriptional activity
  • KEAP1 targets and binds to NFE2L2 for proteosomal degradation
  • under unstressed conditions, serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of NFE2L2, but NFE2L2 is stabilized when KEAP1 is inactivated under oxidative/electrophilic stress conditions
  • MAPK7 interacts with NFE2L2 to induce its nuclear translocation and transcriptional activity
  • AMER1, PALB2, and SQSTM1 bind KEAP1 to activate NFE2L2
  • RXRA interacts physically with NFE2L2 in cancer cells (RXRA diminishes cytoprotection by NFE2L2 by binding directly to the newly defined Neh7 domain in NFE2L2)
  • overexpression of NFE2L2 suppressed THOC1 promoter activity in an ARE-dependent manner
  • USP15 negatively regulates NFE2L2 through deubiquitination of KEAP1
  • JDP2 associates with NFE2L2 and MAFK (NFE2L2-MAFK) to increase the transcription of antioxidant response element-dependent genes
  • JDP2 bound directly to the ARE core sequence, associated with NFE2L2 and MAFK (NFE2L2-MAFK) via basic leucine zipper domains, and increased DNA-binding activity of the NFE2L2-MAFK complex to the ARE and the transcription of ARE-dependent genes
  • HACE1 plays a role in the NFE2L2 antioxidative stress response pathway and in neurodegeneration
  • in oxidative stress, nuclear HMOX1 interacts with NFE2L2 and stabilizes it from GSK3B-mediated phosphorylation coupled with ubiquitin-proteasomal degradation
  • AXIN1 and NFE2L2 physically associated in a protein complex that was regulated by WNT3A, involving the central region of AXIN1 and the Neh4/Neh5 domains of NFE2L2
  • CACUL1/CAC1 is a positive regulator of the NFE2L2 pathway
  • NFE2L2 may be a crucial regulator that mediates PBK/TOPK-exerted promotion of cell proliferation
  • HAMP regulation is inextricably linked to the acute stress response through NFE2L2 signaling
  • low expression of HOTAIR in the spermatozoa of patients with asthenozoospermia and oligoasthenozoospermia, which resulted in down-regulation of NFE2L2 expression
  • PSMD10 interact with the Kelch domain of KEAP1 and effectively competed with NFE2L2 for KEAP1 binding
  • directly IL36G stimulates proliferation of keratinocytes, and it induces expression of keratinocyte mitogens in fibroblasts, suggesting that the NFE2L2-IL36G axis promotes keratinocyte proliferation through a double paracrine loop
  • in addition to regulating NFE2L2, RCBTB1 might exert other functions
  • SIRT2 maintains cellular iron levels by binding to and deacetylating nuclear factor erythroid-derived 2-related factor 2 (NFE2L2) on lysines 506 and 508, leading to a reduction in total and nuclear NFE2L2 levels
  • depletion of NFE2L2 or PGAM5, but not KEAP1, inhibits mitochondrial retrograde trafficking induced by proteasome inhibition
  • cell & other
    REGULATION
    activated by oxidative stress
    by MyD88 dependent signaling induced by lipopolysaccharide is an important intrinsic mechanism that limits excessive inflammation
    repressed by Kelch-like ECH-associated protein 1 (KEAP1)
    ATF3 (a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (NFE2L2)-regulated stress pathway)
    Phosphorylated by protein kinase C
    Other regulated by KEAP1, a key regulatory protein that mediates ubiquitination and degradation of NFE2L2 in the cytoplasm
    neuron–astrocyte interactions also play a key role in the regulation of brain NFE2L2 signaling
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral       gain of function
    in lung cancers
    tumoral       gain of function
    constitutive NFE2L2 activation might cause drug resistance in tumours
    constitutional     --low  
    resulted in decreased HDAC2 in lung, and increased inflammatory lung response which was not reversed by steroid
    Susceptibility to acute lung injury
    Variant & Polymorphism SNP increasing the risk of acute lung injury
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    inhibition of NFE2L2 could be used to enhance chemotherapeutic sensitivity
    respiratorylung 
    NFE22 targeting might provide clinical benefit by reducing both oxidative stress and inflammation in COPD (chronic obstructive pulmonary disease)
    digestive  
    Nrf2 activation by synthetic triterpenoids is a promising candidate target to protect the gastrointestinal tract against acute ionizing radiation
    osteoarticularboneothers
    KEAP1-NFE2L2 axis may be a therapeutic target for the treatment of bone destructive disease
    reproductionfertility 
    therapeutic intervention targeting PARK7 for the treatment of asthenozoospermia
    ANIMAL & CELL MODELS
  • Nrf2(-/-) mice were highly susceptible to N-acetyl-p-aminophenol treatment and died of liver failure
  • mice targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia due to increased sequestration of damaged erythrocytes .
  • Nrf2-deficient mice show decolourization of the incisors
  • Disruption of the Nrf2 gene in mice led to earlier-onset and more extensive cigarette smoke-induced emphysema
  • Disruption of Nrf2 dramatically increased the mortality of mice in response to endotoxin- and cecal ligation and puncture-induced septic shock
  • Nrf2-deficient mice developed tumors more readily in response to carcinogen exposure and caloric exposure was ineffective in suppressing tumors in the KO mice
  • expression levels of NRF1 is significantly decreased in both Alzheimer's disease hippocampal tissues and AD-causing amyloid precursor protein mutant cells
  • Nrf2-null mice develop diffuse white matter injury without overt loss of neurons