Not only membrane proteins surviving the first checkpoint are controlled for their luminal domains, also soluble proteins are inspected by this pathway as they are entirely luminal and thus bypass the first checkpoint. If a lesion in the luminal domains is detected, the involved protein is processed for ERAD using a set of factors including the vesicular trafficking machinery that transports misfolded proteins from the endoplasmic reticulum to the Golgi apparatus.
Proteins that remain within the endoplasmic reticulum after the initial checkpoint are checked for their luminal domains. Soluble proteins, which are entirely luminal, also pass through this pathway. If a defect is found in the luminal domain of a protein, it triggers ERAD, a process involving vesicular trafficking machinery to transport misfolded proteins from the endoplasmic reticulum to the Golgi apparatus.