The Unfolded Protein Response

The unfolded protein response (UPR) is triggered when misfolded proteins accumulate in the endoplasmic reticulum faster than ER-associated degradation (ERAD) pathways can clear them. This proteotoxic stress activates three transmembrane sensor proteins—IRE1, PERK, and ATF6—which detect misfolded proteins through their luminal domains and initiate cellular stress responses to restore protein homeostasis.

IRE1 and PERK are transmembrane stress sensors that respond differently to ER stress. Activated IRE1 dimers signal the nucleus to upregulate chaperone production for accurate protein folding. Activated PERK dimers phosphorylate eIF2α, stalling protein synthesis. Together, these sensors balance protein synthesis and refolding to clear misfolded proteins from the ER.

ATF6 is a transmembrane UPR sensor that responds to misfolded protein accumulation through vesicular transport from the ER membrane to the Golgi complex. There, its cytosolic N-terminal domain is cleaved and released as a transcription factor. This domain binds ER response elements to activate genes encoding ER chaperones and export of misfolded proteins out of the ER.

During UPR activation, the cell upregulates synthesis of ER chaperones including BiP, lectins, and protein disulfide isomerase. These chaperones assist in either refolding misfolded proteins or facilitating their transport back to the cytosol for degradation through ERAD pathways, helping restore protein homeostasis in the ER.

Under normal conditions, ERAD operates at low levels to clear misfolded proteins. When ERAD cannot handle excessive misfolded protein accumulation, the UPR is activated to upscale clearance mechanisms. Active IRE1 upregulates ERAD machinery synthesis, while ATF6 activates genes encoding ER chaperones and retrotranslocation components needed for efficient protein export and degradation.

If UPR activation fails to restore cellular homeostasis and misfolded proteins continue accumulating, the cell triggers apoptotic programs through JNK protein kinase and caspases. This programmed cell death prevents the accumulation of toxic protein aggregates that could damage the cell and surrounding tissues.

The three UPR sensors—IRE1, PERK, and ATF6—use complementary signaling modes to manage ER stress. IRE1 upregulates chaperone production, PERK stalls protein synthesis to reduce ER load, and ATF6 activates genes for ER chaperones and ERAD machinery. Together, they balance protein synthesis and refolding to clear misfolded proteins and restore ER function.