Co-Activation of PKC-δ by CRIF1 Modulates Oxidative Stress in Bone Marrow Multipotent Mesenchymal Stromal Cells after Irradiation by Phosphorylating NRF2 Ser40.
Co-Activation of PKC-δ by CRIF1 Modulates Oxidative Stress in Bone Marrow Multipotent Mesenchymal Stromal Cells after Irradiation by Phosphorylating NRF2 Ser40.
复制标题
CRIF1 共激活 PKC-delta 通过磷酸化 NRF2 Ser40 调节照射后骨髓多能间充质基质细胞中的氧化应激。
作者：
Chen L;Ran Q;Xiang Y;Xiang L;Chen L;Li F;Wu J;Wu C;Li Z
急性放射综合征（h-ARS）造血功能障碍引起的全血细胞减少症和多器官衰竭相关的高死亡率迫切需要制定更有效的治疗策略。在这里，我们发现骨髓多能间充质基质细胞（BMMSCs）有效调节辐射损伤后的氧化应激，这可能是由于辐射诱导cr6相互作用因子1（CRIF1）和核因子e2相关因子2（NRF2）蛋白水平升高。crif1敲低的BMMSCs在辐照后表现出氧化应激和凋亡的增加，部分原因是NRF2核易位减少介导的抗氧化反应受到抑制。共免疫沉淀（Co-IP）实验表明，CRIF1与蛋白激酶C-δ (PKC-δ)相互作用。即使存在三种PKC激动剂，NRF2 Ser40磷酸化在缺乏CRIF1的BMMSCs中也被抑制，这表明CRIF1可能共同激活PKC-δ使NRF2 Ser40磷酸化。辐射损伤后，BMMSCs对hsc体外集落形成能力的支持作用降低，CRIF1缺失加重了这种损伤。由此可见，CRIF1在PKC-δ/NRF2通路调节中发挥重要作用，缓解辐射损伤后BMMSCs的氧化应激，并在一定程度上维持辐射损伤后BMMSCs对hsc的支持作用。
The high mortality associated with pancytopenia and multi-organ failure resulting from hematopoietic disorders of acute radiation syndrome (h-ARS) creates an urgent need for developing more effective treatment strategies. Here, we showed that bone marrow multipotent mesenchymal stromal cells (BMMSCs) effectively regulate oxidative stress following radiative injury, which might be on account of irradiation-induced elevation of protein levels of CR6-interacting factor 1(CRIF1) and nuclear factor E2-related factor 2(NRF2). Crif1-knockdown BMMSCs presented increased oxidative stress and apoptosis after irradiation, which were partially due to a suppressed antioxidant response mediated by decreased NRF2 nuclear translocation. Co-immunoprecipitation (Co-IP) experiments indicated that CRIF1 interacted with protein kinase C-δ (PKC-δ). NRF2 Ser40 phosphorylation was inhibited in Crif1-deficient BMMSCs even in the presence of three kinds of PKC agonists, suggesting that CRIF1 might co-activate PKC-δ to phosphorylate NRF2 Ser40. After radiative injury, the supporting effect of BMMSCs for the colony forming ability of HSCs in vitro was reduced, and the deficiency of CRIF1 aggravated such damage. Thus, CRIF1 plays an essential role in PKC-δ/NRF2 pathway modulation to alleviate oxidative stress in BMMSCs after irradiative injury, and at some level it may maintain the HSCs-supporting effect of BMMSCs after radiative injuries.