Figure 2.

ER-associated degradation (ERAD). ERAD is the conserved protein quality-control machinery of the ER for eliminating misfolded, unassembled, or tightly regulated proteins via the cytosolic ubiquitin proteasome system (UPS). Substrate recognition. Proteins failing to acquire their adequate conformation are recognized by substrate recognition factors such as osteosarcoma 9 (OS-9) for ERAD (substrate recognition). Retrotranslocation and ubiquitination. Once the substrate is recognized, it is subject to retrotranslocation and ubiquitination. Recognition of the substrate accelerates the assembly of the retrontranslocon and the initiation of substrate polyubiquitination via the sequential enzymatic system of ubiquitin E1-activating, ubiquitin E2-conjugating, and ubiquitin E3 ligase. Proteasomal degradation. The retrotranslocated substrate is eventually guided to the proteasome, thereby leading to its degradation (proteasomal degradation). Black arrow, facilitation; red line, misfolded/unfolded protein.