Makio Tadashi, Chen Junsheng, Simmen Thomas
Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G2H7, Alberta, Canada.
Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G2H7, Alberta, Canada.
Cell Calcium. 2024 Dec;124:102961. doi: 10.1016/j.ceca.2024.102961. Epub 2024 Oct 18.
Endoplasmic reticulum (ER) stress is triggered upon the interference with oxidative protein folding that aims to produce fully folded, disulfide-bonded and glycosylated proteins, which are then competent to exit the ER. Many of the enzymes catalyzing this process require the binding of Ca ions, including the chaperones BiP/GRP78, calnexin and calreticulin. The induction of ER stress with a variety of drugs interferes with chaperone Ca binding, increases cytosolic Cathrough the opening of ER Ca channels, and activates store-operated Ca entry (SOCE). Posttranslational modifications (PTMs) of the ER Ca handling proteins through ER stress-dependent phosphorylation or oxidation control these mechanisms, as demonstrated in the case of the sarco/endoplasmic reticulum ATPase (SERCA), inositol 1,4,5 trisphosphate receptors (IPRs) or stromal interaction molecule 1 (STIM1). Their aim is to restore ER Ca homeostasis but also to increase Ca transfer from the ER to mitochondria during ER stress. This latter function boosts ER bioenergetics, but also triggers apoptosis if ER Ca signaling persists. ER Ca toolkit oxidative modifications upon ER stress can occur within the ER lumen or in the adjacent cytosol. Enzymes involved in this redox control include ER oxidoreductin 1 (ERO1) or the thioredoxin-family protein disulfide isomerases (PDI) and ERp57. A tight, but adaptive connection between ER Ca content, ER stress and mitochondrial readouts allows for the proper functioning of many tissues, including skeletal muscle, the liver, and the pancreas, where ER stress either maintains or compromises their function, depending on its extent and context. Upon mutation of key regulators of ER Ca signaling, diseases such as muscular defects (e.g., from mutated selenoprotein N, SEPN1/SELENON), or diabetes (e.g., from mutated PERK) are the result.
内质网（ER）应激是在氧化蛋白折叠受到干扰时触发的，氧化蛋白折叠旨在产生完全折叠、二硫键结合和糖基化的蛋白质，这些蛋白质随后能够离开内质网。许多催化这一过程的酶需要钙离子的结合，包括伴侣蛋白BiP/GRP78、钙连蛋白和钙网蛋白。用多种药物诱导内质网应激会干扰伴侣蛋白与钙的结合，通过内质网钙通道的开放增加胞质钙，并激活储存操纵性钙内流（SOCE）。内质网应激依赖性磷酸化或氧化对内质网钙处理蛋白的翻译后修饰（PTM）控制着这些机制，肌浆网/内质网ATP酶（SERCA）、肌醇1,4,5-三磷酸受体（IPR）或基质相互作用分子1（STIM1）的情况就是如此。其目的是恢复内质网钙稳态，但也会在内质网应激期间增加钙从内质网向线粒体的转移。后一种功能增强了内质网生物能量学，但如果内质网钙信号持续存在，也会触发细胞凋亡。内质网应激时内质网钙工具的氧化修饰可发生在内质网腔或相邻的胞质溶胶中。参与这种氧化还原控制的酶包括内质网氧化还原酶1（ERO1）或硫氧还蛋白家族蛋白二硫键异构酶（PDI）和内质网蛋白57。内质网钙含量、内质网应激和线粒体读数之间紧密但适应性的联系允许许多组织正常运作，包括骨骼肌、肝脏和胰腺，内质网应激在这些组织中根据其程度和背景维持或损害其功能。内质网钙信号关键调节因子发生突变时，会导致诸如肌肉缺陷（例如，由硒蛋白N突变，SEPN1/SELENON）或糖尿病（例如，由PERK突变）等疾病。
