Eggleton Paul, Bremer Edwin, Dudek Elzbieta, Michalak Marek
a Institute of Biomedical and Clinical Science , University of Exeter Medical School , Exeter Devon , UK.
b Department of Surgery , University Medical Center Groningen, University of Groningen , Groningen , The Netherlands.
Expert Opin Ther Targets. 2016 Sep;20(9):1137-47. doi: 10.1517/14728222.2016.1164695. Epub 2016 Mar 25.
Calreticulin is an endoplasmic reticulum (ER) resident protein critical for maintaining Ca(2+) homeostasis and glycoprotein folding in the ER. The protein has also been identified on the cell surface of apoptotic and necrotic cells and implicated to play a role in immunogenic cell death and other extracellular functions. The molecular events that promote cell surface association of calreticulin are not clear. Under cell stress conditions (environmental, drug induced, hypoxia), calreticulin may be upregulated as it attempts to regulate cell survival, death or repair. The initial signaling mechanisms involved in these processes may be regulated by the unfolded protein response (UPR) and genome damage response (GDR) pathways.
Here, the phenomenon of cell surface calreticulin and its extracellular functions are discussed, with a major emphasis on the process of immunogenic cell death. The evidence of how cell surface calreticulin may act as a damage associated molecular pattern molecule is evaluated, in addition to how these properties of the protein can be exploited for therapeutic vaccine development, cancer treatment and mediating other inflammatory processes. In addition, clarification of calreticulin functions from its intracellular, cell surface, and extracellular locations are provided.
While the protein folding and immune-stimulatory properties of calreticulin can be exploited to develop therapies, the molecular pathways involved remain to be elucidated. Nevertheless, exploiting the multifaceted properties of calreticulin may in the future provide a means to treat a number of diseases.
钙网蛋白是一种内质网驻留蛋白，对维持内质网中的Ca(2+) 稳态和糖蛋白折叠至关重要。该蛋白也已在凋亡和坏死细胞的细胞表面被鉴定出来，并被认为在免疫原性细胞死亡和其他细胞外功能中发挥作用。促进钙网蛋白细胞表面结合的分子事件尚不清楚。在细胞应激条件下（环境、药物诱导、缺氧），钙网蛋白可能会上调，因为它试图调节细胞存活、死亡或修复。这些过程中涉及的初始信号机制可能受未折叠蛋白反应（UPR）和基因组损伤反应（GDR）途径调控。
本文讨论了细胞表面钙网蛋白现象及其细胞外功能，主要侧重于免疫原性细胞死亡过程。评估了细胞表面钙网蛋白如何作为一种损伤相关分子模式分子的证据，以及该蛋白的这些特性如何用于治疗性疫苗开发、癌症治疗和介导其他炎症过程。此外，还对钙网蛋白在细胞内、细胞表面和细胞外位置的功能进行了阐释。
虽然钙网蛋白的蛋白质折叠和免疫刺激特性可用于开发治疗方法，但其涉及的分子途径仍有待阐明。然而，利用钙网蛋白的多方面特性未来可能为治疗多种疾病提供一种手段。
