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Glucose on the sugar side chains of proteins keeps unfolded proteins in the ER. Mannoses on sugar side chains act as a timer for protein folding. Unfolded proteins in the ER are threaded through a retrotranslocon into the cytosol where they are ubiquitylated and digested. IRE1, ATF6 and PERK sense the amount of unfolded protein and generates several responses to reduce the effects and amount of unfolded protein.
The Sec pathway transports proteins from the cytoplasm to the periplasm in an unfolded state; consequently, proteins that require a cytoplasmic environment and/or cytoplasmic components for folding, or reach their native state before they interact with the Sec proteins, are not compatible with the Sec pathway.