ERAD and ERAD tuning: disposal of cargo and of ERAD regulators from the mammalian ER

The endoplasmic reticulum (ER) is the site of maturation for secretory and membrane proteins in eukaryotic cells. Unsuccessful folding attempts are eventually interrupted and most folding-defective polypeptides are dislocated across the ER membrane and degraded by cytosolic proteasomes in a complex series of events collectively defined as ER-associated degradation (ERAD). Uncontrolled ERAD activity might prematurely interrupt ongoing folding programs. At steady state, this is prevented by ERAD tuning, that is, the removal of select ERAD regulators from the ER and their degradation by proteasomes and by endo-lysosomal proteases. In Coronaviruses infected cells, the formation of LC3-I coated vesicles containing ERAD regulators cleared from the ER lumen is co-opted to anchor viral replication and transcription complexes to ER-derived membranes.