1. Cell Biology
Download icon

Proteasomes: Nrf1 to the rescue

  1. Jin Ye  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  • Cited 1
  • Views 798
  • Annotations
Cite this article as: eLife 2014;3:e02062 doi: 10.7554/eLife.02062


When the level of proteasomal activity in a cell drops off, a transcription factor called Nrf1 travels to the nucleus to activate the genes that code for proteasomes.

Main text

Proteasomes are protein complexes that play an important role in cells by breaking down proteins that are damaged or are not needed, thus allowing the amino acids in the proteins to be recycled to make new proteins. Sometimes the proteins that need to be broken down are in the cytosol, and sometimes they are bound to the membrane of the endoplasmic reticulum—the organelle inside which strings of amino acids are folded to make proteins. The process through which the latter proteins are broken down is known as endoplasmic reticulum-associated degradation.

Now, in eLife, Senthil Radhakrishnan, Willem den Besten and Raymond Deshaeis of the California Institute of Technology report that endoplasmic reticulum-associated degradation is also involved in the production of proteasomes to begin with (Radhakrishnan et al., 2014). This involvement happens via a transcription factor called Nrf1 that controls the transcription of the genes that encode the various subunits within the proteasome. The Caltech group shows that, under normal circumstances, this transcription factor is always degraded by the proteasomes. However, when the level of proteasomal activity within the cell drops, the transcription factor can travel to the nucleus of the cell and kick start production of more proteasomes—a phenomenon known as ‘bounce back’.

Endoplasmic reticulum-associated degradation begins with enzymes on this organelle adding small proteins called ubiquitins to the proteins that need to be broken down. However, the proteasomes are found in the cytosol of the cell, not the endoplasmic reticulum, so the proteins that have been ubiquitinated must somehow be brought together with the proteasomes to allow the degradation process to take place. To make this happen the parts of the proteins that are located inside the endoplasmic reticulum undergo a process called retrotranslocation—which is catalyzed by a protein called p97—that moves them to the cytosol (Vembar and Brodsky, 2008). Once the ubiquitinated proteins are exposed to the proteasomes in the cytosol, the process of breaking them down can begin.

The transcription factor Nrf1 is also produced within the endoplasmic reticulum and contains an NH2-terminal domain at one end and a COOH-terminal basic leucine zipper (bZip) domain at the other end (Figure 1). The bZip domain is the part of Nrf1 that activates transcription of the genes that encode the various subunits within the proteasome.

Nrf1 and the regulation of proteasome synthesis.

The transcription factor Nrf1 contains an NH2-terminal domain (NTD) that directs it into the lumen of the endoplasmic reticulum (ER) and allows it to interact with the membrane of the ER (shown in yellow). Nrf1 also contains a COOH-terminal basic leucine zipper domain (bZip) that can activate the transcription of certain genes. (A) Under normal circumstances, the enzyme p97 catalyzes the retrotranslocation of Nrf1 so that the bZip domain is in the cytosol, which results in the whole protein being rapidly degraded by proteasomes. (B) When proteasome inhibitors are added to the cell, the retrotranslocated Nrf1 is cleaved by an unidentified enzyme. This allows the bZip domain to leave the membrane and enter the nucleus, where it activates transcription of the genes that encode the various subunits within the proteasome.

Figure credit: Nancy Heard and Jin Ye

The Caltech group showed that, under normal conditions, the bZip domain of the protein was retrotranslocated from the endoplasmic reticulum to the cytosol, where it was rapidly degraded by the proteasomes. This process happened continuously, which meant that the bZip domain never reached the target genes in the nucleus of the cell (Figure 1A). However, when the cells were treated with a proteasome inhibitor, the amount of retrotranslocated Nrf1 (and hence the amount of bZip in the cytosol) increased, which allowed an unidentified enzyme to cleave the transcription factor between the NH2-terminal domain and the bZip domain. Since the bZip domain was no longer attached to the membrane of the endoplasmic reticulum, it was able to enter the nucleus and activate transcription of genes encoding the proteasome subunits (Figure 1B). This mechanism allows cells to sense any reduction in the activity of proteasomes and to compensate for this by increasing the synthesis of new proteasomes.

The work of the Caltech group is significant as it reveals the signaling mechanism that regulates proteasome synthesis. This knowledge should be useful in developing novel strategies to treat diseases in which abnormal proteasomal activity is involved. For example, neurodegenerative diseases such as Parkinson’s disease and various Prion diseases are characterized by the accumulation of ubiquitinated protein aggregates in neurons, which suggests that there too little proteasomal activity within these cells (Lehman, 2009). Is the expression or activation of Nrf1 impaired in these neurons? If so, will activation of the Nrf1 signaling pathway help to eliminate these aggregates? Future studies to address these questions may yield desperately needed novel strategies to combat these diseases by increasing proteasome synthesis.

Treating certain cancers, on the other hand, will require the opposite approach. Proteasome inhibitors have been used to treat multiple myeloma by blocking the degradation of proteins that inhibit the proliferation of cancer cells (Mahindra et al., 2012). Although this treatment is effective at first, nearly all patients eventually relapse because the increased expression of proteasome subunits in the cancer cells leads to drug resistance. Therefore, inhibiting the activation of Nrf1 might make such treatment more effective. This could be done by targeting p97, the protein that catalyzes the retrotranslocation process: however, p97 performs multiple functions inside cells (Halawani and Latterich, 2006), so a better target would be the unidentified enzyme that cleaves Nrf1. Identification of this enzyme is, therefore, a clear priority for future research.


Article and author information

Author details

  1. Jin Ye

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Competing interests
    The author declares that no competing interests exist.

Publication history

  1. Version of Record published: January 21, 2014 (version 1)


© 2014, Ye

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 798
    Page views
  • 77
  • 1

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    Ian F Price et al.
    Research Article Updated

    The germ line produces gametes that transmit genetic and epigenetic information to the next generation. Maintenance of germ cells and development of gametes require germ granules—well-conserved membraneless and RNA-rich organelles. The composition of germ granules is elusive owing to their dynamic nature and their exclusive expression in the germ line. Using Caenorhabditis elegans germ granule, called P granule, as a model system, we employed a proximity-based labeling method in combination with mass spectrometry to comprehensively define its protein components. This set of experiments identified over 200 proteins, many of which contain intrinsically disordered regions (IDRs). An RNA interference-based screen identified factors that are essential for P granule assembly, notably EGGD-1 and EGGD-2, two putative LOTUS-domain proteins. Loss of eggd-1 and eggd-2 results in separation of P granules from the nuclear envelope, germline atrophy, and reduced fertility. We show that IDRs of EGGD-1 are required to anchor EGGD-1 to the nuclear periphery while its LOTUS domains are required to promote the perinuclear localization of P granules. Taken together, our work expands the repertoire of P granule constituents and provides new insights into the role of LOTUS-domain proteins in germ granule organization.

    1. Cell Biology
    Natalya Pashkova et al.
    Research Article

    Attachment of ubiquitin (Ub) to cell surface proteins serves as a signal for internalization via clathrin-mediated endocytosis (CME). How ubiquitinated membrane proteins engage the internalization apparatus remains unclear. The internalization apparatus contains proteins such as Epsin and Eps15, which bind Ub, potentially acting as adaptors for Ub-based internalization signals. Here we show that additional components of the endocytic machinery including CALM, HIP1R, and Sla2 bind Ub via their N-terminal ANTH domain, a domain belonging to the superfamily of ENTH and VHS domains. Structural studies revealed that Ub binds with µM affinity to a unique C-terminal region within the ANTH domain not found in ENTH domains. Functional studies showed that combined loss of Ub-binding by ANTH-domain proteins and other Ub-binding domains within the yeast internalization apparatus caused defects in the Ub-dependent internalization of the GPCR Ste2 that was engineered to rely exclusively on Ub as an internalization signal. In contrast, these mutations had no effect on the internalization of Ste2 engineered to use an alternate Ub-independent internalization signal. These studies define new components of the internalization machinery that work collectively with Epsin and Eps15 to specify recognition of Ub as an internalization signal.