ER-associated degradation (ERAD). (a) ERAD functions to eliminate terminally misfolded, unassembled, or tightly regulated proteins by the cytosolic ubiquitin proteasome system (UPS). (1) Protein translocation into the ER through translocon. (2) Protein folding and maturation. Proteins translocated into the ER are subject to cotranslational and posttranslational folding. (3) Substrate recognition. Proteins failing to acquire their native conformation are recognized for ERAD. (4) Retrotranslocation and ubiquitination. Recognition of ERAD substrates facilitates the assembly of retrotranslocon and initiates ERAD E3 ubiquitin ligase-mediated polyubiquitination of substrates. (5) Proteasomal degradation. Carbohydrate and ubiquitin chains are removed from the retrotranslocated substrates. The retrotranslocated substrates are then inserted into the narrow channel of the proteasome, resulting in the degradation of substrates. (b) Retrotranslocation. ERAD substrate is recruited to retrotranslocon complex, which involves SEL1L, OS-9, Derlin, E3 ubiquitin ligase, and p97/Npl4/Ufd1 complex. Blue pentagon indicates N-glycan and green circle indicates ubiquitin.