A cell under ER stress activates the unfolded protein response (UPR). Which branch of the UPR, if unresolved, triggers CHOP-mediated transcriptional activation of pro-apoptotic genes?

• A IRE1 branch activating XBP1 splicing
• B PERK branch phosphorylating eIF2alpha, inducing ATF4 and then CHOP ✓
• C ATF6 branch trafficking to Golgi for processing
• D ERAD pathway retrotranslocating misfolded proteins to the cytosol

Explanation

The PERK (PKR-like ER kinase) branch phosphorylates eIF2alpha, globally reducing protein translation to decrease ER burden, but also selectively upregulates ATF4 translation. ATF4 transcribes CHOP (C/EBP homologous protein), a pro-apoptotic transcription factor that induces BIM, downregulates BCL-2, and drives caspase activation if ER stress is irresolvable. The IRE1/XBP1 and ATF6 branches primarily boost protein folding and ERAD capacity. ERAD is a protein quality-control mechanism, not a UPR signalling branch per se.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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