Endoplasmic-reticulum-associated protein degradation

Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome. The process of ERAD can be divided into three steps: The recognition of misfolded or mutated proteins depends on the detection of substructures within proteins such as exposed hydrophobic regions, unpaired cysteine residues and immature glycans. In mammalian cells for example, there exists a mechanism called glycan processing. In this mechanism, the lectin-type chaperones calnexin/calreticulin (CNX/CRT) provide immature glycoproteins the opportunity to reach their native conformation. They can do this by way of reglucosylating these glycoproteins by an enzyme called UDP-glucose-glycoprotein glucosyltransferase also known as UGGT. Terminally misfolded proteins, however, must be extracted from CNX/CRT. This is carried out by members of the EDEM (ER degradation-enhancing α-mannosidase-like protein) family (EDEM1-3) and ER mannosidase I. This mannosidase removes one mannose residue from the glycoprotein and the latter is recognized by EDEM. Eventually EDEM will target the misfolded glycoproteins for degradation by facilitating binding of ERAD lectins OS9 and XTP3-B. Because the ubiquitin–proteasome system (UPS) is located in the cytosol, terminally misfolded proteins have to be transported from the endoplasmic reticulum back into cytoplasm. Most evidence suggest that the Hrd1 E3 ubiquitin-protein ligase can function as a retrotranslocon or dislocon to transport substrates into the cytosol. Hrd1 is not required for all ERAD events, so it is likely that other proteins contribute to this process. For example, glycosylated substrates are recognized by the E3 Fbs2 lectin. Further, this translocation requires a driving force that determines the direction of transport. Since polyubiquitination is essential for the export of substrates, it is widely thought that this driving force is provided by ubiquitin-binding factors.

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Ubiquitin-conjugating enzyme

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Endoplasmic-reticulum-associated protein degradation

Cytosol

vignette|Diagramme d'une cellule : 1. Nucléole 2. Noyau 3. Ribosome 4. Vésicule 5. Réticulum endoplasmique rugueux (ou granuleux), aussi appelé ergastoplasme 6. Appareil de Golgi 7. Cytosquelette 8. Réticulum endoplasmique lisse 9. Mitochondrie 10. Vacuole dans les cellules végétales 11. Cytosol 12. Lysosome dans les cellules animales 13. Centriole Le cytosol ou cytosole est, en biologie cellulaire, la phase liquide dans laquelle baignent les organites cytoplasmiques présents à l'intérieur des cellules.

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