Protein: Endoplasmic reticulum membrane sensor NFE2L1 (Locus control region-factor 1) (LCR-F1) (Nuclear factor erythroid 2-related factor 1) (NF-E2-related factor 1) (NFE2-related factor 1) (Nuclear factor, erythroid derived 2, like 1) (Protein NRF1, p120 form) (Transcription factor 11) (TCF-11) [Cleaved into: Transcription factor NRF1 (Protein NRF1, p110 form)] (Q14494)
Organism: Homo sapiens (Human)
Function: Endoplasmic reticulum membrane sensor that translocates into the nucleus in response to various stresses to act as a transcription factor. Constitutes a precursor of the transcription factor NRF1 (By similarity). Able to detect various cellular stresses, such as cholesterol excess, oxidative stress or proteasome inhibition. In response to stress, it is released from the endoplasmic reticulum membrane following cleavage by the protease DDI2 and translocates into the nucleus to form the transcription factor NRF1 (By similarity). Acts as a key sensor of cholesterol excess: in excess cholesterol conditions, the endoplasmic reticulum membrane form of the protein directly binds cholesterol via its CRAC motif, preventing cleavage and release of the transcription factor NRF1, thereby allowing expression of genes promoting cholesterol removal, such as CD36 (By similarity). Involved in proteasome homeostasis: in response to proteasome inhibition, it is released from the endoplasmic reticulum membrane, translocates to the nucleus and activates expression of genes encoding proteasome subunits.
Subcellular location: [Endoplasmic reticulum membrane sensor NFE2L1]: Endoplasmic reticulum membrane {ECO:0000269|PubMed:16687406, ECO:0000269|PubMed:24448410, ECO:0000269|PubMed:24998528}; Single-pass type II membrane protein {ECO:0000269|PubMed:20932482, ECO:0000269|PubMed:24448410}. Endoplasmic reticulum membrane {ECO:0000269|PubMed:16687406, ECO:0000269|PubMed:24448410, ECO:0000269|PubMed:24998528}; Single-pass type III membrane protein {ECO:0000269|PubMed:20932482, ECO:0000269|PubMed:24448410}. Note=In normal conditions, probably has a single-pass type II membrane protein topology, with the DNA-binding domain facing the endoplasmic reticulum lumen (PubMed:24448410). Following cellular stress, it is rapidly and efficiently retrotranslocated to the cytosolic side of the membrane, a process dependent on p97/VCP, to have a single-pass type III membrane protein topology with the major part of the protein facing the cytosol (PubMed:24448410). Retrotranslocated proteins are normally rapidly degraded by the proteasome and active species do not accumulate (PubMed:24448410). However, retrotranslocated protein NFE2L1 escapes degradation and is cleaved at Leu-104 by DDI2, releasing the protein from the endoplasmic reticulum membrane and forming the transcription factor NRF1 that translocates into the nucleus (PubMed:24448410). {ECO:0000269|PubMed:24448410}.; SUBCELLULAR LOCATION: [Transcription factor NRF1]: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00978, ECO:0000269|PubMed:16687406, ECO:0000269|PubMed:20932482, ECO:0000269|PubMed:24998528, ECO:0000269|PubMed:27528193}. Note=Translocates into the nucleus following cleavage of Endoplasmic reticulum membrane sensor NFE2L1 by aspartyl protease DDI2. {ECO:0000269|PubMed:24448410, ECO:0000269|PubMed:27528193}.
Interaction partners:
- Transcription factor MafG
- Transcription factor MafF
- Transcription factor Maf
- Transcription factor MafK
- Kelch-like ECH-associated protein 1
- Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
- Protein DDI1 homolog 2
Sequence:
MLSLKKYLTEGLLQFTILLSLIGVRVDVDTYLTSQLPPLREIILGPSSAYTQTQFHNLRNTLDGYGIHPKSIDLDNYFTARRLLSQVRALDRFQVPTTEVNAWLVHRDPEGSVSGSQPNSGLALESSSGLQDVTGPDNGVRESETEQGFGEDLEDLGAVAPPVSGDLTKEDIDLIDILWRQDIDLGAGREVFDYSHRQKEQDVEKELRDGGEQDTWAGEGAEALARNLLVDGETGESFPAQVPSGEDQTALSLEECLRLLEATCPFGENAEFPADISSITEAVPSESEPPALQNNLLSPLLTGTESPFDLEQQWQDLMSIMEMQAMEVNTSASEILYSAPPGDPLSTNYSLAPNTPINQNVSLHQASLGGCSQDFLLFSPEVESLPVASSSTLLPLAPSNSTSLNSTFGSTNLTGLFFPPQLNGTANDTAGPELPDPLGGLLDEAMLDEISLMDLAIEEGFNPVQASQLEEEFDSDSGLSLDSSHSPSSLSSSEGSSSSSSSSSSSSSSASSSASSSFSEEGAVGYSSDSETLDLEEAEGAVGYQPEYSKFCRMSYQDPAQLSCLPYLEHVGHNHTYNMAPSALDSADLPPPSALKKGSKEKQADFLDKQMSRDEHRARAMKIPFTNDKIINLPVEEFNELLSKYQLSEAQLSLIRDIRRRGKNKMAAQNCRKRKLDTILNLERDVEDLQRDKARLLREKVEFLRSLRQMKQKVQSLYQEVFGRLRDENGRPYSPSQYALQYAGDGSVLLIPRTMADQQARRQERKPKDRRK