Misfolded proteins in the ER are subject to the ER-associated degradation (ERAD) pathway. Misfolded proteins are recognized by various ER factors, such as chaperones, and directed toward ER membrane E3 ubiquitin-ligases. The three main ligases identified are RMA1, HRD1, and TEB4. Each ligase is part of a complex with an E2 ubiquitin-conjugating enzyme and other factors. Substrate proteins are ubiquitylated, extracted into the cytoplasm via a p97 AAA + ATPase-dependent process, and degraded by the proteasome.