Xu S, Xu Y, Chen L, Fang Q, Song S, Chen J, Teng J
Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing, China.
Center for Quantitative Biology, Peking University, Beijing, China.
Oncogenesis. 2017 Mar 20;6(3):e304. doi: 10.1038/oncsis.2017.6.
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) receptor type 1 (IPR1) 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 IPR1 and decreases the UPR, thereby inhibiting ER stress-induced apoptosis.
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，该反应在早期可减轻应激，若稳态在较长时间内无法恢复，则会触发细胞凋亡。在此，我们报告称，CREC家族成员网钙蛋白1（RCN1）在ER应激期间被核因子κB（NF-κB）反式激活，并抑制ER应激诱导的细胞凋亡。RCN1的缺失通过激活蛋白激酶R样内质网激酶-CCAAT/增强子结合蛋白同源蛋白（PERK-CHOP）信号通路，在药物诱导的ER应激期间增加UPR，从而诱导细胞凋亡。此外，我们发现RCN1的前两个EF手型钙结合基序与其内质网腔结构域第3环上的1,4,5-三磷酸肌醇（IP）受体亚型1（IPR1）特异性相互作用，并抑制内质网钙释放和细胞凋亡。总之，这些数据表明，作为NF-κB靶点的RCN1通过与IPR1结合来抑制内质网钙释放，并降低UPR，从而抑制ER应激诱导的细胞凋亡。
