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When the ER-associated degradation or ERAD pathways work inefficiently, misfolded proteins accumulate in the ER and trigger the unfolded protein response or UPR.

UPR uses three transmembrane proteins, IRE1, ATF6, and PERK, as stress sensors.

These sensors detect misfolded proteins through their luminal domains and are activated. They then accelerate the clearance of misfolded proteins by relaying distress signals to the nucleus and cytoplasm.

After activation, the dimerized IRE1 signals the nucleus to upregulate chaperone production to assist in accurate protein folding.

Additionally, piled-up misfolded proteins initiate vesicular transport of ATF6 from the ER membrane to the cisternal membrane of the Golgi complex, where its cytosolic N-terminal domain is cleaved.

The released protein domain acts as a transcription factor and binds the ER response elements responsible for activating cellular protein folding and ERAD pathways.

On the contrary, activated PERK dimers phosphorylate and inhibit the eukaryotic translation initiation factor 2 alpha or eIF2ɑ, stalling protein synthesis.

Together, the activated UPR sensors use different modes to balance the synthesis and refolding of prote