Ubiquitylation in the ERAD Pathway

Ubiquitylation is a protein modification mechanism, which is found in a multitude of cellular processes like DNA repair and replication, cell signaling, intracellular trafficking and also, very prominently, in selective protein degradation. One specific protein degradation event in the cell concerns the elimination of misfolded proteins to prevent disastrous malfunctioning of cellular pathways. The most complex of these ubiquitylation dependent elimination pathways of misfolded proteins is associated with the endoplasmic reticulum (ER). Proteins, which enter the endoplasmic reticulum for secretion, are folded in this organelle and transported to their site of action. A rigid protein quality control check retains proteins in the endoplasmic reticulum, which fail to fold properly and sends them back to the cytosol for elimination by the proteasome. This requires crossing of the misfolded protein of the endoplasmic reticulum membrane and polyubiquitylation in the cytosol by the ubiquitin-activating, ubiquitin-conjugating and ubiquitin-ligating enzyme machinery.