Protein folding in the ER is assisted by molecular chaperones. Accumulation of misfolded proteins in the ER triggers the unfolded protein response (UPR). Which ER transmembrane sensor activates XBP1 mRNA splicing (non-canonical splicing) as part of UPR?

• A PERK (PKR-like ER kinase) — phosphorylates eIF2α
• B ATF6 — a transcription factor released by S1P/S2P proteases
• C IRE1α (inositol-requiring enzyme 1 alpha) — an endoribonuclease that splices XBP1 mRNA ✓
• D GRP78/BiP — the master ER chaperone that senses misfolded protein accumulation

Explanation

The UPR has three main branches: (1) IRE1α — its kinase activity auto-phosphorylates, activating its endoribonuclease domain, which performs unconventional cytoplasmic splicing of XBP1 mRNA, removing a 26-nt intron to produce spliced XBP1s (sXBP1), a transcription factor upregulating ER chaperones and ERAD genes; (2) PERK — phosphorylates eIF2α, reducing global translation but selectively increasing ATF4; (3) ATF6 — translocates to Golgi, is cleaved by S1P/S2P to release ATF6f, which activates chaperone genes. GRP78/BiP is the master chaperone that sequesters all three sensors during normal function; when misfolded proteins accumulate, BiP dissociates from the sensors, activating them.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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