XPO1-mediated nuclear export of RNF146 protects from angiotensin II-induced endothelial cellular injury

Abstract Endothelial cells death induced by angiotensin II (Ang II) plays a role in vascular injury. RNF146 is identified as a E3 ubiquitin ligase, which promotes cell survival under many types of stresses. However, the role of RNF146 in endothelial cellular injury is unknown. In human umbilical vein endothelial cells (HUVECs), Ang II treatment led to cell death by oxidative stress and promoted RNF146 to accumulate in nucleus in time dependent manner. Nuclear export signal was found in the RNF146's sequence. The interaction between RNF146 and XPO1 was further confirmed by co-immunoprecipitation. Inhibition of XPO1 with KPT-185 increased the level of RNF146 in nucleus. The expression of XPO1 was suppressed responding to Ang II treatment. Overexpression of XPO1 facilitated the nuclear shuttling of RNF146, which protected from Ang II-induced cell death. Moreover, overexpression of RNF146 in HUVECs reduced the cell death induced by Ang II, whereas inhibition of XPO1 abolished the protective effect of RNF146. Therefore, our data demonstrated that RNF146 was a protective factor against cell death induced by AngII in human endothelial cells, which was dependent on XPO1-mediated nuclear export.