Theranostics 2017; 7(10):2634-2648. doi:10.7150/thno.17853
Co-Activation of PKC-δ by CRIF1 Modulates Oxidative Stress in Bone Marrow Multipotent Mesenchymal Stromal Cells after Irradiation by Phosphorylating NRF2 Ser40
1. Department of Blood Transfusion, Radiation Biology Laboratory, The Second Affiliated Hospital, Third Military Medical University, Chongqing 400038, China
2. General Hospital of Xinjiang Military Area Command, Urumqi 830000, China
* Equal contribution to this work
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.
Keywords: h-ARS, BMMSCs, Oxidative Stress, Irradiation, CRIF1, NRF2, PKC-δ.
Chen L, Ran Q, Xiang Y, Xiang L, Chen L, Li F, Wu J, Wu C, Li Z. Co-Activation of PKC-δ by CRIF1 Modulates Oxidative Stress in Bone Marrow Multipotent Mesenchymal Stromal Cells after Irradiation by Phosphorylating NRF2 Ser40. Theranostics 2017; 7(10):2634-2648. doi:10.7150/thno.17853. Available from http://www.thno.org/v07p2634.htm