Checkpoints in ER-associated degradation: excuse me, which way to the proteasome?

The failure of secreted proteins to fold results in their retrotranslocation from the endoplasmic reticulum (ER) and degradation by the proteasome in a process called ‘ER-associated degradation’ (ERAD). Two recent studies indicate that ERAD substrates are targeted to different pathways depending on the topology of the substrate and the subcellular location of the misfolded domain.