CCN1/CYR61 overexpression in hepatic stellate cells induces ER stress-related apoptosis
CCN1/CYR61 overexpression in hepatic stellate cells induces ER stress-related apoptosis
复制标题
DOI：
10.1016/j.cellsig.2015.10.013
复制
发表时间：
2016-01-01
影响因子：
4.8
通讯作者：
Weiskirchen, Ralf
中科院分区：
文献类型：
--
作者：
Borkham-Kamphorst, Erawan;Steffen, Bettina T.;Weiskirchen, Ralf
CCN1/CYR61是CCN家族的一种基质细胞蛋白，包含六种与细胞外基质（ECM）特异性相关的分泌蛋白。CCN1通过诱导肌成纤维细胞衰老来防止增生性瘢痕形成，从而作为皮肤伤口愈合过程的增强剂。在肝纤维化中，衰老细胞主要来源于活化的肝星状细胞（HSC），这些细胞最初因肝损伤而增殖，并且是细胞外基质的主要来源。我们在此研究通过腺病毒基因转染原代肝星状细胞、肌成纤维细胞（MFB）和永生化肝星状细胞系（即LX - 2、CFSC - 2G），将CCN1用作衰老诱导剂以减轻肝纤维化的可能性。用Ad5 - CMV - CCN1感染在所有这些细胞中诱导产生大量CCN1蛋白，导致内质网（ER）过载以及代偿性未折叠蛋白反应（UPR）。未折叠蛋白反应导致内质网伴侣蛋白包括BIP/Grp78、Grp94上调，并导致IRE1α激活，这可由具有IRE1α诱导的JNK磷酸化的剪接XBP1 mRNA证明。未折叠蛋白反应的PERK和eIF2α臂被磷酸化，同时伴有显著的CHOP上调。Ad5 - CMV - CCN1诱导肝星状细胞凋亡，这通过半胱天冬酶 - 12、半胱天冬酶 - 9和执行蛋白酶半胱天冬酶 - 3的蛋白水解切割以及TUNEL阳性染色得以证明。值得注意的是，Ad5 - CMV - CCN1有效地降低了I型胶原蛋白mRNA的表达和蛋白水平。我们得出结论，基质细胞蛋白CCN1基因转染通过内质网应激和未折叠蛋白反应诱导肝星状细胞凋亡。（C）2015作者。由爱思唯尔公司出版。
CCN1/CYR61 is a matricellular protein of the CCN family, comprising six secreted proteins specifically associated with the extracellular matrix (ECM). CCN1 acts as an enhancer of the cutaneous wound healing process by preventing hypertrophic scar formation through induction of myofibroblast senescence. In liver fibrosis, the senescent cells are primarily derived from activated hepatic stellate cells (HSC) that initially proliferate in response to liver damage and are the major source of ECM. We investigate here the possible use of CCN1 as a senescence inducer to attenuate liver fibrogenesis by means of adenoviral gene transfer in primary HSC, myofibroblasts (MFB) and immortalized HSC lines (i.e. LX-2, CFSC-2G). Infection with Ad5-CMV-CCN1 induced large amounts of CCN1 protein in all these cells, resulting in an overload of the endoplasmic reticulum (ER) and in a compensatory unfolded protein response (UPR). The UPR resulted in upregulation of ER chaperones including BIP/Grp78, Grp94 and led to an activation of IRE1 alpha as evidenced by spliced XBP1 mRNA with IRE1 alpha-induced JNK phosphorylation. The UPR arm PERK and eIF2a was phosphorylated, combined with significant CHOP upregulation. Ad5-CMV-CCN1 induced HSC apoptosis that was evident by proteolytic cleavage of caspase-12, caspase-9 and the executor caspase-3 and positive TUNEL stain. Remarkably, Ad5-CMV-CCN1 effectively reduced collagen type I mRNA expression and protein. We conclude that the matricellular protein CCN1 gene transfer induces HSC apoptosis through ER stress and UPR. (C) 2015 The Authors. Published by Elsevier Inc.