Owusu Benjamin Y, Zimmerman Kurt A, Murphy-Ullrich Joanne E
Department of Pathology, University of Alabama at Birmingham, G001A Volker Hall, Birmingham, AL, 35294, USA.
Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
J Cell Commun Signal. 2018 Mar;12(1):289-299. doi: 10.1007/s12079-017-0426-2. Epub 2017 Oct 28.
Endoplasmic reticulum (ER) stress is a key factor contributing to fibrotic disease. Although ER stress is a short-term adaptive response, with chronic stimulation, it can activate pathways leading to fibrosis. ER stress can induce TGF-β signaling, a central driver of extracellular matrix production in fibrosis. This review will discuss the role of an ER protein, calreticulin (CRT), which has both chaperone and calcium regulatory functions, in fibrosis. CRT expression is upregulated in multiple different fibrotic diseases. The roles of CRT in regulation of fibronectin extracellular matrix assembly, extracellular matrix transcription, and collagen secretion and processing into the extracellular matrix will be discussed. Evidence for the importance of CRT in ER calcium release and NFAT activation downstream of TGF-β signaling will be presented. Finally, we will summarize evidence from animal models in which CRT expression is genetically reduced or experimentally downregulated in targeted tissues of adult animals and discuss how these models define a key role for CRT in fibrotic diseases.
内质网（ER）应激是导致纤维化疾病的关键因素。尽管内质网应激是一种短期适应性反应，但在慢性刺激下，它可激活导致纤维化的信号通路。内质网应激可诱导转化生长因子-β（TGF-β）信号传导，这是纤维化过程中细胞外基质产生的核心驱动因素。本综述将讨论一种具有伴侣和钙调节功能的内质网蛋白——钙网蛋白（CRT）在纤维化中的作用。CRT表达在多种不同的纤维化疾病中上调。将讨论CRT在调节纤连蛋白细胞外基质组装、细胞外基质转录以及胶原蛋白分泌和加工成细胞外基质中的作用。还将展示CRT在TGF-β信号下游内质网钙释放和活化T细胞核因子（NFAT）中的重要性证据。最后，我们将总结来自动物模型的证据，在这些模型中，成年动物的靶组织中CRT表达通过基因手段降低或实验性下调，并讨论这些模型如何确定CRT在纤维化疾病中的关键作用。
