RCN1 suppresses ER stress-induced apoptosis via calcium homeostasis and PERK-CHOP signaling.
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 (IP3) receptor type 1 (IP3R1) 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 IP3R1 and decreases the UPR, thereby inhibiting ER stress-induced apoptosis.
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.
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Xu
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.
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Xu
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.
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Chen
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.
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Fang
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.
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Song
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.
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Chen
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.
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Teng