未折叠蛋白反应
内质网
内质网相关蛋白降解
细胞生物学
蛋白质稳态
神经退行性变
生物
综合应力响应
信号转导
蛋白激酶R
EIF-2激酶
蛋白激酶A
激酶
翻译(生物学)
生物化学
医学
丝裂原活化蛋白激酶激酶
疾病
病理
信使核糖核酸
基因
细胞周期蛋白依赖激酶2
作者
Naoki Hiramatsu,Wei‐Chieh Chiang,Timothy D. Kurt,Christina J. Sigurdson,Jonathan H. Lin
标识
DOI:10.1016/j.ajpath.2015.03.009
摘要
Eukaryotic cells fold and assemble membrane and secreted proteins in the endoplasmic reticulum (ER), before delivery to other cellular compartments or the extracellular environment. Correctly folded proteins are released from the ER, and poorly folded proteins are retained until they achieve stable conformations; irreparably misfolded proteins are targeted for degradation. Diverse pathological insults, such as amino acid mutations, hypoxia, or infection, can overwhelm ER protein quality control, leading to misfolded protein buildup, causing ER stress. To cope with ER stress, eukaryotic cells activate the unfolded protein response (UPR) by increasing levels of ER protein-folding enzymes and chaperones, enhancing the degradation of misfolded proteins, and reducing protein translation. In mammalian cells, three ER transmembrane proteins, inositol-requiring enzyme-1 (IRE1; official name ERN1), PKR-like ER kinase (PERK; official name EIF2AK3), and activating transcription factor-6, control the UPR. The UPR signaling triggers a set of prodeath programs when the cells fail to successfully adapt to ER stress or restore homeostasis. ER stress and UPR signaling are implicated in the pathogenesis of diverse diseases, including neurodegeneration, cancer, diabetes, and inflammation. This review discusses the current understanding in both adaptive and apoptotic responses as well as the molecular mechanisms instigating apoptosis via IRE1 and PERK signaling. We also examine how IRE1 and PERK signaling may be differentially used during neurodegeneration arising in retinitis pigmentosa and prion infection.
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