KPNB1 , XPO7 and IPO8 Mediate the Translocation of NF‐κB /p65 into the Nucleus

NF‐κB /p65 is retained in the cytoplasm until it is activated in response to stress. Nuclear import of p65 is regulated by importin α in a nuclear localization signal ( NLS )‐dependent manner. However, the role of importin β family members in the nuclear translocation of p65 is largely unclear. In this study, using high‐content siRNA screening, we identified three of 17 importin β family members that are involved in the nuclear import of p65. Our data showed that knockdown of KPNB1 , XPO7 and IPO8 reduced the amount of nuclear p65 following tumor necrosis factor‐α ( TNF ‐α) stimulation, resulting in lower NF‐κB activity. KPNB1 was the major importin β receptor for p65 import, and this import was dependent on the NLS of p65. However, NLS ‐mutated p65 still entered the nucleus and bound to XPO7 and IPO8 . Interestingly, among the six members of the importin α family, KPNA2 was most important for p65 import. Taken together, our results show that the import of p65 mainly relies on the canonical KPNA2 / KPNB1 pathway; however, p65 is also imported by an alternative pathway that is independent of its NLS . Redundant importin receptors are likely to maintain the important function of p65 according to need .