RCN1 suppresses ER stress-induced apoptosis via calcium homeostasis and PERK-CHOP signaling
RCN1 suppresses ER stress-induced apoptosis via calcium homeostasis and PERK-CHOP signaling
复制标题
RCN1 通过钙稳态和 PERK-CHOP 信号传导抑制 ER 应激诱导的细胞凋亡
DOI：
10.1038/oncsis.2017.6
复制
发表时间：
2017
期刊：
影响因子：
6.2
通讯作者：
Teng J.
中科院分区：
文献类型：
--
作者：
Xu S.;Xu Y.;Chen L.;Fang Q.;Song S.;Chen J.;Teng J.
内质网（ER）应激是由内质网稳态紊乱引起的，会导致未折叠蛋白反应（UPR）的激活，从而在早期缓解应激，如果稳态长期失效则引发细胞凋亡。在这里，我们报道了 CREC 家族成员 reticulocalbin 1 (RCN1) 在 ER 应激期间被核因子 kappa B (NF-κB) 反式激活，并抑制 ER 应激诱导的细胞凋亡。 RCN1 的缺失通过激活 PRKR 样 ER 激酶 -CCAAT/增强子结合蛋白同源蛋白 (PERK-CHOP) 信号传导来增加药物诱导的 ER 应激期间的 UPR，从而诱导细胞凋亡。此外，我们发现RCN1的前两个EF手钙结合基序与其ER管腔结构域环3上的肌醇1,4,5-三磷酸（IP 3）受体1型（IP 3 R1）特异性相互作用，并抑制ER钙释放和细胞凋亡。总之，这些数据表明，NF-κB 的靶标 RCN1 通过与 IP 3 R1 结合抑制 ER 钙释放并降低 UPR，从而抑制 ER 应激诱导的细胞凋亡。
Endoplasmic reticulum (ER) stress is caused by the disturbance of ER homeostasis and leads to the activation of the unfolded protein response (UPR), which alleviates stress at an early stage and triggers apoptosis if homeostasis fails over a prolonged timeframe. Here, we report that reticulocalbin 1 (RCN1), a member of the CREC family, is transactivated by nuclear factor kappa B (NF-κB) during ER stress and inhibits ER stress-induced apoptosis. The depletion of RCN1 increases the UPR during drug-induced ER stress by activating PRKR-like ER kinase–CCAAT/enhancer-binding protein-homologous protein (PERK–CHOP) signaling, thus inducing apoptosis. Furthermore, we found that the first two EF-hand calcium-binding motifs of RCN1 specifically interact with inositol 1, 4, 5-trisphosphate (IP 3) receptor type 1 (IP 3 R1) on loop 3 of its ER luminal domain and inhibit ER calcium release and apoptosis. Together, these data indicate that RCN1, a target of NF-κB, suppresses ER calcium release by binding to IP 3 R1 and decreases the UPR, thereby inhibiting ER stress-induced apoptosis.