NFE2L1

Key takeaways

NFE2L1 belongs to biology; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect NFE2L1 to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of NFE2L1 from memory before moving on to harder problems.

Reference excerpt

Nuclear factor erythroid 2-related factor 1 (Nrf1) also known as nuclear factor erythroid-2-like 1 (NFE2L1) is a protein that in humans is encoded by the NFE2L1 gene. Since NFE2L1 is also referred to as Nrf1, it is often confused with nuclear respiratory factor 1. NFE2L1 is a cap 'n' collar, basic-leucine zipper (bZIP) transcription factor. Several isoforms of NFE2L1 have been described for both human and mouse genes. NFE2L1 was first cloned in yeast using a genetic screening method. NFE2L1 is ubiquitously expressed, and high levels of transcript are detected in the heart, kidney, skeletal muscle, fat, and brain. Four separate regions — an asparagine/serine/threonine, acidic domains near the N-terminus, and a serine-rich domain located near the CNC motif — are required for full transactivation function of NFE2L1. NFE2L1 is a key regulator of cellular functions including oxidative stress response, differentiation, inflammatory response, metabolism, cholesterol handling and maintaining proteostasis.

Interactions NFE2L1 binds DNA as heterodimers with one of small Maf proteins (MAFF, MAFG, MAFK). NFE2L1 has been shown to interact with C-jun.

Cellular homeostasis NFE2L1 regulates a wide variety of cellular responses, several of which are related to important aspects of protection from stress stimuli. NFE2L1 is involved in providing cellular protection against oxidative stress through the induction of antioxidant genes. The glutathione synthesis pathway is catalyzed by glutamate-cysteine ligase, which contains the catalytic GCLC and regulatory GCLM, and glutathione synthetase (GSS). NFE2L1 was found to regulate Gclm and Gss expression in mouse fibroblasts. Gclm was found to be a direct target of NFE2L1. NFE2L1 also regulates Gclc expression through an indirect mechanism. NFE2L1 knockout mice also exhibit down-regulation of Gpx1-, Hmox1-, and NFE2L1-deficient hepatocytes from liver-specific NFE2L1 knockout mice showed decreased expression of various Gst genes. Metallothioenein-1 and Metallothioenein-2 genes, which protect cells against cytotoxicity induced by toxic metals, are also direct targets of NFE2L1. NFE2L1 is also involved in maintaining proteostasis. Brains of mice with conditional knockout of NFE2L1 in neuronal cells showed decreased proteasome activity and accumulation of ubiquitin-conjugated proteins, and down regulation of genes encoding the 20S core and 19S regulatory sub-complexes of the 26S proteasome. A similar effect on proteasome gene expression and function was observed in livers of mice with NFE2L1 conditional knockout in hepatocytes. Induction of proteasome genes was also lost in brains and livers of NFE2L1 conditional knockout mice. Re-establishment of NFE2L1 function in NFE2L1 null cells rescued proteasome expression and function, indicating NFE2L1 was necessary for induction of proteasome genes (bounce-back response) in response to proteasome inhibition. This compensatory up-regulation of proteasome genes in response to proteasome inhibition has also been demonstrated to be NFE2L1-dependent in various other cell types. NFE2L1 was shown to directly bind and activate expression of the PsmB6 gene, which encodes a catalytic subunit of the 20S core. In the retina, it was shown that NFE2L1 overexpression increases and knockout reduces proteasomal levels and activity. NFE2L1 was also shown to regulate expression of Herpud1 and Vcp/p97, which are components of the ER-associated degradation pathway. NFE2L1 also plays a role in metabolic processes. Loss of hepatic NFE2L1 has been shown to result in lipid accumulation, hepatocellular damage, cysteine accumulation, and altered fatty acid composition. Glucose homeostasis and insulin secretion have also been found to be under the control of NFE2L1. Insulin-regulated glycolytic genes—Gck, Aldob, Pgk1, and Pklr, hepatic glucose transporter gene — SLC2A2, and gluconeogenic genes — Fbp1 and Pck1 were repressed in livers of NFE2L1 transgenic mice. NFE2L1 may also play a role in maintaining chromosomal stability and genomic integrity by inducing expression of genes encoding components of the spindle assembly and kinetochore. NFE2L1 has also been shown to sense and respond to excess cholesterol in the ER.

Regulation NFE2L1 is an ER membrane protein. Its N-terminal domain (NTD) anchors the protein to the membrane. Specifically, amino acid residues 7 to 24 are known to be a hydrophobic domain that serves as a transmembrane region. The concerted mechanism of HRD1, a member of E3-ubiquitin ligase family, and p97/VCP1 was found to play an important role in the degradation of NFE2L1 through the ER Associated Degradation (ERAD) pathway and the release of NFE2L1 from the ER membrane. NFE2L1 is also regulated by other ubiquitin ligases and kinases. FBXW7, a member of the SCF ubiquitin ligase family, targets NFE2L1 for proteolytic degradation by the proteasome. FBXW7 requires the Cdc4 phosphodegron domain within NFE2L1 to be phosphorylated via Glycogen Kinase 3. Casein Kinase 2 was shown to phosphorylate Ser497 of NFE2L1, which attenuates the activity of NFE2L1 on proteasome gene expression. NFE2L1 also interacts with another member of the SCF ligase ubiquitin family known as β-TrCP. β-TrCP also binds to the DSGLC motif, a highly conserved region of CNC-bZIP proteins, in order to polyubiquitinate NFE2L1 prior to its proteolytic degradation. Phosphorylation of Ser599 by protein kinase A enables NFE2L1 and C/EBP-β to dimerize to repress DSPP expression during odontoblast differentiation. NFE2L1 expression and activation is also controlled by cellular stresses. Oxidative stress induced by arsenic and t-butyl hydroquinone leads to accumulation of the NFE2L1 protein inside the nucleus as well as higher activation on antioxidant genes. Treatment with an ER stress inducer, tunicamycin, was shown to induce accumulation of NFE2L1 inside the nucleus; however, it was not associated with increased activity, suggesting further investigation is needed to explain the role of ER stress on NFE2L1. Hypoxia was also shown to increase the expression of NFE2L1 while attenuating expression of the p65 isoform of NFE2L1. Growth factors affect expression of NFE2L1 through an mTORC and SREBP-1 mediated pathway. Growth factors induce higher activity of mTORC, which then promotes activity of its downstream protein SREBP-1, a transcription factor for NFE2L1.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with NFE2L1

Start with the simplest possible case. Write down what NFE2L1 claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to NFE2L1 before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about NFE2L1 ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of NFE2L1

In research: NFE2L1 appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses NFE2L1 in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: NFE2L1 is common in secondary-school and first-year university syllabi. It links to neighbouring topics Genes on human chromosome 17, Transcription factors, Wikipedia articles with corresponding academic peer reviewed articles, so understanding it makes those chapters shorter.
In everyday life: Look for NFE2L1 outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study NFE2L1 in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what NFE2L1 means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain NFE2L1 out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is NFE2L1 in simple terms?

Nuclear factor erythroid 2-related factor 1 (Nrf1) also known as nuclear factor erythroid-2-like 1 (NFE2L1) is a protein that in humans is encoded by the NFE2L1 gene. Since NFE2L1 is also referred to as Nrf1, it is often confused with nuclear respiratory factor 1.

Why does NFE2L1 matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study NFE2L1?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on NFE2L1.