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HSPA5/GRP78/BiP The accumulation of unfolded or misfolded proteins in the ER activates a signaling pathway known as the unfolded protein response (UPRER), which is regulated by three main sensors: protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6)