Endoplasmic-reticulum-associated protein degradation

In this mechanism, the lectin-type chaperones calnexin/calreticulin (CNX/CRT) provide immature glycoproteins the opportunity to reach their native conformation.

Eventually EDEM will target the misfolded glycoproteins for degradation by facilitating binding of ERAD lectins OS9 and XTP3-B.

[1] 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.

Since polyubiquitination is essential for the export of substrates, it is widely thought that this driving force is provided by ubiquitin-binding factors.

The first of these reactions takes place when the ubiquitin-activating enzyme E1 hydrolyses ATP and forms a high-energy thioester linkage between a cysteine residue in its active site and the C-terminus of ubiquitin.

As ERAD is a central element of the secretory pathway, disorders in its activity can cause a range of human diseases.

By losing their function, these components are no longer able to stabilize aberrant proteins, so that the latter accumulate and damage the cell.

HIV uses an efficient mechanism to dislocate a single-membrane-spanning host protein, CD4, from the ER and submits it to ERAD.

The Vpu protein mainly retains the CD4 in the ER by SCFβ-TrCP-dependent ubiquitination of the CD4 cytosolic tail and transmembrane domain (TMD) interactions.

In cells that are infected with HIV, SCFβTrCP interacts with Vpu and ubiquitinates CD4, which is subsequently degraded by the proteasome.