Degradation of Misfolded Secretory and Membrane Proteins and Associated Diseases


Protein homeostasis is maintained through a balance among protein synthesis, folding, assembly and degradation. The latter is crucial also to prevent accumulation of misfolded products in the cell. The conjugation to ubiquitin marks proteins for degradation by the proteasome. Secretory and membrane proteins are monitored for proper folding and oligomerisation in the endoplasmic reticulum (ER). In this compartment, defective proteins are recognised and targeted to the proteasome in a process called ER‐associated protein degradation or ERAD. A first step of retrotranslocation across the ER membrane to the cytosol is required. Ubiquitylation is carried out by ER enzymes and is also functionally intertwined with retrotranslocation. Malfunctioning of ERAD machinery or accumulation of folding‐defective proteins in the ER is associated with various human diseases ranging from neurodegenerative disorders to cancer. The design of drugs that meliorate ERAD or promote protein folding could provide new therapeutic strategies against these diseases.

Key Concepts

  • The ER is the organelle where secretory or membrane proteins are folded and assembled with the aid of chaperones and oxidoreductases before they exit the ER.
  • A quality control inside the ER monitors protein folding, and terminally misfolded or unassembled proteins are selectively recognised and targeted to ERAD.
  • Trimmed N‐glycans of terminally misfolded luminal glycoproteins are signals for recognition as a substrate for degradation.
  • ERAD substrates are sorted to different degradation pathways based on the location of the misfolded region and the topology of the protein.
  • ERAD involves several factors that are organised in modules and cooperate in the processes of substrate recognition, retrotranslocation, ubiquitylation and targeting of substrates to the proteasome where cleavage occurs.
  • The retrotranslocation of the substrates from the ER to the cytosol is mediated by still undefined channel proteins.
  • Retrotranslocated substrates are ubiquitylated on the cytosolic side of the ER by membrane‐associated E3 ubiquitin ligases.
  • In ERAD, ubiquitylation is dynamically interconnected with substrate extraction from the ER membrane, delivery to the proteasome, removal of the N‐glycan chains from glycosylated polypeptides and processing of the substrates for final disposal.
  • Malfunctioning of ERAD components or accumulation of misfolded substrates causes various human diseases.

Keywords: ER; ERAD; proteolysis; ubiquitin; ubiquitylation; proteasome; protein folding; protein trafficking; secretory proteins; membrane proteins; glycosylation

Figure 1. ERAD pathways in yeast. Hrd1p and Doa10p complexes and their known partners are represented. ERAD‐M and ERAD‐L degrade misfolded membrane proteins with misfolded TMDs or luminal soluble proteins via the Hrd1p complex. ERAD‐C degrades integral membrane proteins with a misfolded domain in the cytoplasm via the Doa10p complex. All ERAD pathways require cytosolic Cdc48p for protein translocation and extraction from the ER membranes. The substrate is ubiquitylated during or after translocation and is targeted to the proteasome (PRT) for degradation. Ub, ubiquitin. The classification for the different ERAD pathways also exists in mammalian cells but is less stringent.Reproduced from Lemus and Goder () © U.S. National Library of Medicine, National Institutes of Health.
Figure 2. The CNX/CRT cycle and the generation of the N‐glycan signal for glycoprotein degradation. The main steps are: (1) addition by oligosaccharyltransferase (OST) of an N‐linked oligosaccharide (GlcNac2Man9Glu3) to the nascent polypeptide chain; (2) removal of the first glucose by GluI; association of the deglucosylated polypeptides with malectin, a lectin‐like protein; (3) Removal of the second glucose by GluII; (4) Interaction of monoglucosylated polypeptides with CNX or CRT; (5) Cleavage of the last glucose by GluII; (6) Recognition of the misfolded proteins and reglucosylation of their N‐linked chains by UGT1. The polypeptide enters another round of interaction with CNX or CRT; (7) Export of properly folded proteins through vesicles budded from the ER exit site; (8) Processing of the N‐linked oligosaccharides of terminally misfolded polypeptides by ER mannosidases and (9) targeting of the polypeptides to the proteasome for final disposal. Note: , N‐acetylglucosamine (GlcNac); , Mannose (Man) and , Glucose (Glu). Reproduced with permission from Tannous et al. () © Elsevier.
Figure 3. Organisation of mammalian ERAD. The factors that mediate ERAD are organised into modules. In each module, factors tend to form stable interactions, whereas factors from different modules in general bind in a more dynamic manner. Within the same module factors can also form parallel pathways to mediate the retrotranslocation of different substrates. Specific recognition and recruitment of luminal misfolded proteins (ERAD‐L) and their selective targeting for insertion in the ER membrane occur in modules 1 and 2. Subsequently, ubiquitin conjugation is performed by the ubiquitylation modules 3 and 4. This is followed by extraction from the ER membrane via the AAA+–ATPase p97 complex (module 4). Dislocated products are shuttled to the proteasome, and removal of N‐linked chains by NGly1 facilitates the degradation of glycoprotein substrates (modules 5 and 6). Proteasomes are thought to be brought in proximity of the retrotranslocation site through interaction with ER membranes. The recognition and degradation of ERAD‐M and ERAD‐C substrates do not require the recognition and initiation modules in the ER. The dashed arrows indicate the flow of substrates. Reproduced with permission from Christianson and Ye (). © Nature Publishing Group.


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Further Reading

Bergbold N and Lemberg MK (2013b) Emerging role of rhomboid family proteins in mammalian biology and disease. Biochimica et Biophysica Acta 1828: 2840–2848.

Morimoto RI, Selkoe DJ and Kelly JW (eds) (2011) Protein Homeostasis. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press.

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Kaufman, Randal J, and Popolo, Laura(Jun 2016) Degradation of Misfolded Secretory and Membrane Proteins and Associated Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022577.pub2]