ER stress-unfolded protein response (UPRer)

Correctly folding proteins is a severely complicated process that fails at times, despite the controlled environment of the ER and numerous molecular helpers. Under normal conditions, these misfolded proteins are degraded through the ER-associated degradation (ERAD) mechanism. However, various physiological or environmental stressors can inhibit or overwhelm these normal mechanisms resulting in an increase in the amount of misfolded proteins, which trigger the Unfolded Protein Response (UPR). Organisms have evolved the UPR to handle this ER stress and suppress the toxicity of accumulated misfolded proteins (proteotoxicity). In mammals the UPR attenuates protein synthesis through PERK/PEK1 and increases transcription of folding and ERAD components through activation of potent transcription factors through IRE1 splicing of XBP1 mRNA and ER-stress cleavage of ATF-6. These events ultimately augment folding and enhance degradation capacity of the organelle. In C. elegans, the UPR also activates transcriptional regulators that reduce protein synthesis and increase the number of components necessary to deal with misfolded proteins.

蛋白质的正确折叠过程极为复杂，即使在粗面内质网这一受控环境中，有时也会失败，并有众多分子辅助因子。在正常情况下，这些错误折叠的蛋白质会通过内质网相关降解（ERAD）机制被降解。然而，各种生理或环境应激原可能抑制或压倒这些正常机制，导致错误折叠蛋白质的数量增加，从而触发未折叠蛋白质反应（UPR）。生物体进化出UPR以应对这种内质网应激并抑制积累的错误折叠蛋白质的毒性（蛋白质毒性）。在哺乳动物中，UPR通过PERK/PEK1衰减蛋白质合成，并通过XBP1 mRNA的IRE1剪接和ATF-6的内质网应激切割激活强大的转录因子，从而增加折叠和ERAD成分的转录。这些事件最终增强了折叠能力并提升了该细胞器的降解能力。在秀丽隐杆线虫中，UPR还激活了转录调控因子，以减少蛋白质合成并增加处理错误折叠蛋白质所需的成分数量。