Which cellular response is activated by accumulation of misfolded proteins in the ER?

• A. Apoptosis
• B. Autophagy
• C. Unfolded Protein Response
• D. Necrosis

Answer: (C)

When misfolded proteins build up in the endoplasmic reticulum, the cell activates the unfolded protein response to restore proper folding and proteostasis. Chaperones like BiP bind the misfolded proteins, which releases ER stress sensors (IRE1, PERK, and ATF6) to start signaling. IRE1 splices XBP1 mRNA, producing a transcription factor that upregulates chaperones and components of ER-associated degradation. PERK phosphorylates eIF2α to dampen overall protein synthesis, giving the ER a break while selectively increasing stress-responsive genes via ATF4. ATF6 moves to the Golgi, is cleaved, and then acts as another transcription factor to boost chaperone production and ERAD components. Collectively, these pathways enhance the ER’s protein-folding capacity and its ability to remove misfolded proteins. If the stress remains unresolved, the UPR can tilt toward apoptosis; autophagy can also be engaged as an additional clearance route, but the response specifically initiated by accumulation of misfolded proteins in the ER is the unfolded protein response.