Study of the unfolded protein responses (UPR) is mainly addressed by challenging eukaryotic cells with chemical compounds that impair calcium, redox or glycan homeostasis. These dramatically alter the endoplasmic reticulum (ER) environment and function, but also trigger pleiotropic effects that may result in multi‐organellar failure and cell death. Recent works showed that UPR induced by the accumulation of unfolded polypeptides in the ER lumen drastically differs from chemically induced UPR. Unfolded proteins are tolerated by cells, which activate a finely tuned UPR without entering apoptotic programs. How cells adapt the UPR to the burden of misfolded proteins, what structural features of the accumulating proteins determine UPR intensity and how these mechanisms translate into disease are crucial questions to be address in the future.

中文翻译：

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三个分支来统治他们？UPR 信号响应化学与错误折叠蛋白诱导的内质网应激

未折叠蛋白反应 (UPR) 的研究主要通过用损害钙、氧化还原或聚糖稳态的化合物来挑战真核细胞来解决。这些会显着改变内质网 (ER) 环境和功能，但也会引发多效性效应，可能导致多细胞器衰竭和细胞死亡。最近的工作表明，由内质网腔内未折叠多肽的积累诱导的 UPR 与化学诱导的 UPR 截然不同。细胞可以耐受未折叠的蛋白质，从而在不进入凋亡程序的情况下激活微调的 UPR。细胞如何使 UPR 适应错误折叠蛋白质的负担，积累蛋白质的哪些结构特征决定了 UPR 强度以及这些机制如何转化为疾病是未来需要解决的关键问题。